In a long-awaited — and some would say long-feared — update in the regulatory pathway for FDA approval of follow-on biologics, the Senate’s Senate Health, Education, Labor and Pensions HELP Committee gave the thumbs up to the Biologics Price Competition and Innovation Act of 2007 (S. 1695), which will address the scientific, regulatory and legal issues involved in bringing generic biologics to the marketplace.

Senators Kennedy, Hatch, Clinton, and Enzi introduced the legislation authorizing the FDA to approve a follow-on version of biologic therapies. The legislation includes standards for the FDA to approve follow-on biologics as well as a period of exclusivity for the brand name drug company. The Act amends section 351 of the Public Health Service Act to provide for an approval pathway for safe biosimilar and interchangeable biological products (relying in part on the previous approval of a brand product):

• A biosimilar applicant is required to demonstrate that there are no clinically meaningful differences in safety, purity and potency between its product and the brand product. A demonstration of biosimilarity includes analytical data, animal testing and one or more clinical studies, unless such a requirement is determined by the FDA to be unnecessary.
• The Act provides incentives for the development of both new life-saving biological products and interchangeable biosimilar products: 12 years of data exclusivity for the brand company during which a biosimilar product may not be approved, and 1 year of exclusivity for the first interchangeable biological product.
• The biosimilar applicant must provide its application and information about its manufacturing process to the brand company. A series of informational exchanges then occur in which the biosimilar applicant and the brand company identify patents in question and explain their views as to their validity or infringement.

Senator Kennedy said the committee plans to attach the bill to the Prescription Drug User Fee Act (PDUFA) reauthorization bill. Sen. Sherrod Brown (Go Ohio!) had drafted an amendment that would have shortened the exclusivity period to seven years but withdrew the amendment without a vote.

Biotechnology Industry Organization (BIO) president Jim Greenwood stated that:

Senators Kennedy, Enzi, Clinton and Hatch deserve credit for their hard work in crafting this complex legislation, and for the bipartisan support they have achieved for the bill. Biotechnology innovators share the goal of ensuring all patients have access to life-enhancing and life-saving biologics. We support the development of a pathway for the approval of follow-on biologics.

Toward that goal, we will continue to work with Congress to make certain the legislation is improved to ensure it supports the principles we have outlined for a pathway to follow-on products, namely providing better protections for patient safety and the patient-doctor relationship.

In addition, the patent litigation rules included in the bill must be revised to improve protections for the intellectual property rights of innovators, ensure timely resolution of all patent disputes and maintain incentives to develop future medical breakthroughs.

Earlier, BIO released a set of principles to guide the development of a pathway for the approval of follow-on biologics. BIO also developed a detailed rationale supporting the need for substantial data exclusivity. Meanwhile, generic manufacturers expressed concern that a 12 year exclusivity for the brand company is too long.

The bill will still need to be passed by the full Senate and the House and then signed by the President.

Read the draft legislation here: Biologics Price Competition and Innovation Act of 2007 (S. 1695).

See lawmakers pat themselves on the back here.

Posted June 28th, 2007 by Stephen Albainy-Jenei in Biogenerics, FDA
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David Boundy of Cantor Fitzgerald and Mike Strickland of GlaxoSmithKline attended a meeting with the Office of Management and Budget (OMB) to discuss the USPTO’s Changes to Practice for Continuing Applications, Requests for Continued Examination Practice, and Applications Containing Patentably Indistinct Claims (Fed. Reg. 71: 48-61 (January 3, 2006)). The proposed regulations would limit an applicant’s ability to file no more than one continuation application.

Attendees included John Love and Jennifer McDowell of the USPTO as well as David Rostker, OMB/ Office of Information and Regulatory Affairs, Lisa Branch, OMB/ Office of Information and Regulatory Affairs, Counselor to Administrator Dudley, Aaron Flynn, Office of Science and Technology Policy, and Peter Robbins, Dept. of Commerce, Office of General Counsel.

The conference was in regard to numerous concerns over the implementation of the rule changes, summarized in a letter to the honorable Susan Dudley, Office of Information and Regulatory Affairs (OMB), and signed on behalf of numerous organizations and companies that oppose the changes.

While the USPTO has represented to OMB that these draft final rules are significant under Executive Order 12,866, but not economically significant.

Ah, but “au contraire” says the group. These draft rules should be considered a package because they have important interactive effects: complex patent applications are simultaneously more likely to contain more than 10 independent claims and benefit from continued examination practice to carefully refine the scope of those claims, and the two rules impose burdens and requirements that conflict with each other.

The rule changes meet the test for being economically significant because:

• The rules may have an annual effect on the economy of $100 million or more; and
• The rules may adversely affect in a material way the economy, and in particular, those sectors of the economy that are the engines of technical innovation

The group also USPTO’s alleged violation of the Information Quality Act and Office of Management and Budget’s implementing guidelines; and claimed significant discrepancies were found between the USPTO’s claimed savings in paperwork burden and the increase in actual burden specifically mandated by the Limits on Claims Rule.

The attachments provided to OMB number in the hundreds of pages and allege numerous problems with regard to the manner in which the continuation rule changes were implemented but my personal favorites include:

(a) The PTO apparently did not conduct any studies to identify the source of its backlog problem (See Attachment C4); and
(b) The backlog may well be due to internal disincentives provided to examiners and not any burden imposed on the office by applicants (See Attachment F8-11).

The USPTO’s attitude towards all this can be seen in the comments by John Whealan, the Deputy General Counsel for Intellectual Property Law and Solicitor of USPTO, speaking at a symposium held at Duke University. Whealan acknowledged the increased applicant burden and cited it as a benefit to the patent bar:

“The good news is, for you patent prosecutors out there, your rates should go up, not your rates, but your hours, because this is going to take probably more work to do.”

He also stated the obvious:

“You file 50 [claims,] we’re going to look at ten. . . . We’ll look at the independents, a couple dependents.  If you want all your claims examined up front, you can have it done, but it’s going to cost you, you’re going to have to do some work, which in the current law of inequitable conduct, nobody’s going to want to do.”

(Attachment M2-5).

You can put in your two cents to:

The Honorable Susan E. Dudley
Office of Information and Regulatory Affairs
Office of Management and Budget
Washington, DC 20503
Fax: (202) 395-7245

Look for a lawsuit if the USPTO decides to enact the proposed rule changes.

More at peter zura’s 271 patent blog and the Patent Prospector.

Posted June 27th, 2007 by Stephen Albainy-Jenei in Prosecution, USPTO
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While not as fundamentally important as Bong Hits 4 Jesus, the U.S. Supreme Court declined to hear a case profoundly important to the pharmaceutical industry. For the second time, the Court rebuffed a challenge to a “reverse payments” deal — this one where an AstraZeneca company paid off a Barr Pharmaceuticals company to delay marketing of generic tamoxifen.

Earlier, the Solicitor General’s Office submitted a brief to the Supreme Court urging the Court to deny certiorari in the reverse payment case Joblove v. Barr Labs (S.Ct. No. 06-830). The Supreme Court had asked for the government’s views on the antitrust effects of settlement agreements between holders of drug patents and generic drug makers enjoying the 180-day market exclusivity after Food and Drug Administration approval. This case involves the same legal issue that was raised in FTC v. Schering-Plough Corp., No. 05-273 (Jun. 26, 2006; denying certiorari).

The issue is the appropriate antitrust standard applicable to an agreement between a brand pharmaceutical manufacturer (and patent holder) and a generic market entrant (and alleged patent infringer) whereby the patent holder shares a portion of its future profits with the alleged infringer in exchange for the latter’s agreement to not market its competitive product. The three Circuit Courts of Appeals that have addressed the issue have rendered inconsistent decisions.

Zeneca manufactures and markets tamoxifen citrate (tamoxifen), a drug for the treatment of breast cancer, under the brand-name Nolvadex®. Zeneca’s former parent, Imperial Chemical Industries PLC (ICI), held the patent for tamoxifen, U.S. Patent 4,536,516. In 1987, Barr amended its ANDA for tamoxifen to include a Paragraph IV Certification, which prompted a patent infringement suit by ICI (Zeneca’s parent). In 1992, the ‘516 Patent was held invalid and unenforceable.

While an appeal from the judgment invalidating the patent was pending in the Federal Circuit, Zeneca and ICI, the patent holders, and Barr, the alleged infringer, agreed to settle the case. Zeneca and ICI agreed to: (1) pay Barr $21 million; (2) pay Barr’s supplier $35.9 million; and (3) supply Barr with Zeneca-manufactured tamoxifen for resale in the United States at a high royalty rate. In return, Barr agreed to: (1) abandon its successful challenge of the tamoxifen patent; (2) withdraw its Paragraph IV Certification to manufacture and market generic tamoxifen prior to the patent’s expiration; and, if possible, and (3) prevent competitive entry by future generic manufacturers.

Now, the FTC alleges that the agreements unlawfully restrained competition in the market for tamoxifen in violation of Sections 1 and 2 of the Sherman Act, 15 U.S.C. §§ 1, 2, and analogous state statutes. The question presented being:

“Under what circumstances is an agreement by a brand pharmaceutical manufacturer (and patent holder) to share a portion of its future profits with a generic market entrant (and alleged patent infringer), in exchange for the generic’s agreement not to market its product, a violation of the antitrust laws?”

In FTC v. Schering-Plough, the Solicitor General urged that no conflict existed that would warrant the Court’s review of this issue, based on the same body of case law that exists today.

Oddly, while stating up-front that this case “raises important and complex issues“:

There may be particular reason to be concerned about the competitive consequences of a settlement that includes a substantial payment from the patent holder to the alleged infringer. Such a “reverse payment” can be a device for the sharing of the monopoly rents that are preserved when the alleged infringer is induced to stay out of the relevant market and drop its challenge to the validity of the patent.

and while noting that “the court of appeals adopted an insufficiently stringent standard for scrutinizing patent settlements that include reverse payments”:

The dissenting opinion below correctly suggested that a court reviewing an antitrust challenge to a settlement of a patent infringement claim that includes a reverse payment should apply the rule of reason—and that, in doing so, a court should consider “the strength of the patent as it appeared at the time at which the parties settled.” Pet. App. 125a-126a. The panel majority, however, rejected that approach and instead held that such a settlement would be valid unless (1) the settlement “extend[ed] * * * the monopoly beyond the pat-ent’s scope”; (2) the settlement involved fraud; or (3) the underlying lawsuit was “objectively baseless in the sense that no reasonable litigant could realistically expect success on the merits.” Id. at 52a (internal quotation marks and citation omitted). That standard is erroneous.

The SG turned around and pleaded that “this case does not present a good vehicle for addressing the question presented”:

Although the court of appeals applied an erroneous standard for scrutinizing patent infringement settlements that include reverse payments, this case is not an attractive vehicle for the Court’s consideration of the difficult and context-sensitive questions involved in assessing the legality of such settlements. The federal antitrust claims in this case appear to be moot, the factual setting is atypical and unlikely to recur, and subsequent regulatory changes may undercut one of the theories of competitive harm advanced by petitioners. For those reasons, the petition should be denied.

An official at the U.S. Federal Trade Commission said the FTC remains committed to pursuing cases against reverse payments by pharmaceutical companies that it deems to be anti-competitive. The FTC had filed an appeal but did not file a brief in this case.

See the Solicitor General’s Office Brief.

Posted June 27th, 2007 by Stephen Albainy-Jenei in Generic drugs, FTC
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Senators Kennedy, Hatch, Clinton, and Enzi announced legislation authorizing the FDA to approve a follow-on version of biologic therapies. The legislation, the Biologics Price Competition and Innovation Act of 2007, includes standards for the FDA to approve follow-on biologics as well as a period of exclusivity for the brand name drug company.

The draft compromise bill tries to resolve some of the sticky issues surrounding the extent of trials a follow-on biologic would need prior to approval, whether a biosimilar could be deemed an interchangeable alternative to a brandname biologic, and the length of time an innovator biologic would be protected from competition.

A biologic is manufactured in a living system such as a microorganism, or plant or animal cells. Most biologics are very large, complex molecules or mixtures of molecules while a small molecule drug is typically manufactured through chemical synthesis. It is difficult to characterize a complex biologic by testing methods available in the laboratory. Therefore, for biologics, the product may be too closely tied to the process to separate the two.

Unlike small molecule drugs, which are approved under the FDCA, most biologics are approved under the Public Health Service Act (PHSA). The FDCA provides a framework for approving generic copies of small molecule drugs, but no commensurate legal framework is currently in place for approving follow-on biologics either under the FDCA or under the PHSA. The complexity of biologics makes it impossible to analyze them in a laboratory to the degree possible with chemical drugs, and to show without clinical trials that one biologic has the same safety and effectiveness profile as another.

To be approved as a generic, a drug must have the same active ingredient, strength, dosage form, and route of administration as the reference drug, and it must also be “bioequivalent.” This means that generic drugs are the same chemically as their innovator counterparts and that they act the same way in the body. The bioequivalence of the generic drug is demonstrated through relatively simple analyses such as blood level testing, without the need for human clinical trials. In approving a generic drug under 505(j) of the FDCA, FDA determines that the generic is “therapeutically equivalent” to the innovator drug, and is interchangeable with it.

FDA has stated that it has not determined how interchangeability can be established for complex proteins. Historically, FDA has permitted interchangeability only when two products are “therapeutic equivalents.” However, when the follow-on manufacturer establishes a new manufacturing process, beginning with new starting materials, it will produce a product that is different from and not therapeutically equivalent with that of the innovator. Because of the complexity of biologics, the only way to establish whether there are differences that affect the safety and effectiveness of the follow-on product is to conduct clinical trials.

Recent approvals of follow-on biologics by the FDA have been limited to those few biotechnologically derived products such as human growth hormone and certain insulin products approved under the New Drug Approval provisions of the Food, Drug, and Cosmetic Act, such as Novartis’ Sandoz approval of a 505(b)(2) NDA for its Omnitrope® version of Pfizer’s Genotropin® human growth hormone. While not a true generic application, a 505(b)(2) NDA allowed Sandoz to submit less than a full NDA. The FDA has previously taken the position that it lacks the authority to approve generic biologics under the PHSA.

The Act amends section 351 of the Public Health Service Act to provide for an approval pathway for safe biosimilar and interchangeable biological products (relying in part on the previous approval of a brand product) while preserving the incentives that have fueled the development of these life-saving medicines.

Approval Process

A biosimilar applicant is required to demonstrate that there are no clinically meaningful differences in safety, purity and potency between its product and the brand product. A demonstration of biosimilarity includes analytical data, animal testing and one or more clinical studies, unless such a requirement is determined by the FDA to be unnecessary.

FDA may approve a biosimilar product as interchangeable, meaning it can be substituted for the brand product without the intervention of the health care provider who prescribed it. Showing interchangeability requires evidence that the biosimilar product will produce the same clinical result as the brand product in any given patient and that it presents no additional risk in terms of safety or diminished efficacy if a patient alternates or is switched between products.

The legislation allows, but does not require the FDA to issue guidance documents to inform with the public of the standards and criteria the agency will use in approving biosimilar and interchangeable products. Development of these guidance documents will require public input. Applications can be filed in the absence of guidance documents.

Exclusivities

The Act provides incentives for the development of both new life-saving biological products and interchangeable biosimilar products: 12 years of data exclusivity for the brand company during which a biosimilar product may not be approved, and 1 year of exclusivity for the first interchangeable biological product.

Patent Resolution

The legislation includes a multi-step process to identify and resolve patents that the biosimilar product may infringe. The biosimilar applicant must provide its application and information about its manufacturing process to the brand company. A series of informational exchanges then occur in which the biosimilar applicant and the brand company identify patents in question and explain their views as to their validity or infringement.

The two parties then either agree to a list of these patents to be litigated first or exchange lists when they can’t, and the brand company must then sue the biosimilar applicant within 30 days to defend them. If the brand company wins a final court decision that a patent is valid and infringed by the biosimilar product before the 12 year data exclusivity has run, the court must enjoin infringement of the patent until it expires. For identified patents not included in this initial litigation, the biosimilar applicant must give the brand company notice 180 days before it intends to launch its product, and the brand company may then seek a preliminary injunction to block the launch.

If the brand company fails to identify a patent, it can’t later enforce it against the biosimilar product. If it fails to defend a patent identified for initial litigation, the brand company may only later receive a reasonable royalty. If the biosimilar applicant fails at any step to do what it is required to do, the brand company may immediately defend its patents.

Legal Issues

The FDA has taken the position that each biologic is unique and inexorably linked to and inseparable from the manufacturing processes used in its creation. Complex operational and proprietary details of the manufacturing processes are central to and define the identity and unique molecular safety and effectiveness attributes of each biologic. Even if it were possible to establish “sameness” of biologics without clinical trials, it might be necessary for agency reviewers to examine trade secret data concerning the manufacturing processes of the innovator to perform a comparative assessment about “sameness.”

The bill is likely to be approved by the Senate Health, Education, Labor and Pensions Committee when it meets on June 27th.

Press statement: http://help.senate.gov/Maj_press/2007_06_22_a.pdf

Read the draft legislation here: Biologics Price Competition and Innovation Act

Posted June 26th, 2007 by Stephen Albainy-Jenei in Biogenerics
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In a sign of “piling on”, more than 200 organizations and businesses have signed on to a letter to Chairman Leahy, Chairman Conyers, Chairman Berman, Senator Specter, Representative Smith, and Representative Coble of the Committee on the Judiciary regarding patent reform bill.

The group voiced serious concerns with certain provisions of The Patent Reform Act of 2007, S. 1145 and H.R. 1908 stating that “While we share the goal of making America more innovative and competitive, we find that certain aspects of the legislation will inadvertently accomplish the exact opposite by undermining the value of patents.”

Re-stating concerns with the patent bill, the group urged:

1. Removal of language pertaining to the apportionment of damages;
2. Removal of the open-ended post-grant review process;
3. Removal of rulemaking authority for the Patent and Trademark Office; and
4. The inclusion of a more flexible grace period.

Of particular note are signers:

- Association of University Technology Managers

- Biotechnology Industry Organization

- CropLife America

- Institute of Electrical and Electronics Engineers (IEEE-USA)

- Medical Device Manufacturers Association

- NanoBusiness Alliance

- Small Business Exporters Association of the United States

- Small Business Technology Council

- Center for Small Business and the Environment

- Multiple small and large businesses, universities and venture capital funds.

See the full letter here:  200 Letter on Patent Reform

Posted June 20th, 2007 by Stephen Albainy-Jenei in Patent Reform
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The U.S. Court of Appeals for the Federal Circuit held that claims with a means plus function limitation – here a “control means” — where there is no corresponding structure described in the specification, are invalid. See, Biomedino, LLC v. Waters Technologies Corporation (2006-1350).

Biomedino, LLC had appealed from a lower court decision that claims 13-17 and 40 of U.S. Pat. No. 6,602,502 are invalid for indefiniteness under 35 U.S.C. § 112 para. 2.

Essentially this case asks the question: for purposes of § 112 para 6, is sufficient corresponding structure disclosed when the specification simply recites that a claimed function can be performed by known methods or using known equipment where prior art of record and the testimony of experts suggest that known methods and equipment exist?

The court concluded that the inquiry is whether one of skill in the art would understand the specification itself to disclose a structure, not simply whether that person would be capable of implementing a structure.

Section 112, 6 of Title 35 of the United States Code permits an applicant to express a claim limitation as a means or step for performing a specified function without claiming the structure that performs the function:

An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.

In Valmont Industries, Inc. v. Reinke Manufacturing Co., the Federal Circuit held that § 112, 6 permitted “broad means-plus-function language, but provided a standard to make the broad claim language more definite[: ] . . . [t]he applicant must describe in the patent specification some structure which performs the specified function.” 983 F.2d 1039, 1543 (Fed. Cir. 1993).

The claim at issue is:

13. A device comprising a passage; binding means in said device for binding a species substantially specifically, said binding means being in fluid communication with said passage; exposure means in said device for exposing said species to said binding means and for preventing said binding means from leaving said device; closed regeneration means for separating said species from said binding means for reuse of said binding means in said device; valving for selectively connecting said closed regeneration means in fluid communication with said binding means, and control means for automatically operating said valving.

The district court held that if a claim element contains the term “means” and recites a function, there is a presumption that § 112, 6 applies. After deciding that the word “control” did not identify any structure in particular, the district court looked to the specification. However, the only references in the specification to the “control means” are a box labeled “Control” in Figure 6 and a statement that the regeneration process of the invention “may be controlled automatically by known differential pressure, valving and control equipment.”

From this, the district court concluded:

The specification says nothing more than that unspecified equipment may be used to control the regeneration process. The fact that one skilled in the art could envision various types of equipment capable of automatically operating valves does not change the fact that no structure capable of performing that function was disclosed by the inventor.

Therefore, the court held that “[t]he failure to disclose a structure corresponding to the ‘control means’ function makes claims 13-17 and claim 40 of indefinite scope in violation of § 112, 2 of the Patent Act.”

Biomedino argued that use of the term “control” to describe “means” takes the phrase “control means” outside of § 112, 6 asserting that “control means” recites sufficient structure on its own such that it obviates the need for § 112, 6. Basically, Biomedino argued that a “control” is a precise structure well understood by those of skill in the art, and thus, the word “means” in claims 13 and 40 can be ignored. Additionally, Biomedino tried to argue that “control” is analogous to the term “controller” and conveys, to one skilled in the art, structure for controlling the valves and other equipment.

Unfortunately, the Federal Circuit just wasn’t buying their revisionist history. The Court went against the patentee stating that:

When a claim uses the term “means” to describe a limitation, a presumption inheres that the inventor used the term to invoke § 112, 6. Altiris, Inc. v. Symantec Corp., 318 F.3d 1367, 1375 (Fed. Cir. 2003). “This presumption can be rebutted when the claim, in addition to the functional language, recites structure sufficient to perform the claimed function in its entirety.” Id. Claims 13 and 40 recite no such structure. As the district court noted, the “reference to ‘control’ is simply an adjective describing ‘means:’ [sic] it is not a structure or material capable of performing the identified function.” Biomedino, slip op. at 12. We agree with the district court and hold that Biomedino has not rebutted the presumption that § 112, 6 applies to “control means.”

Once a court concludes that a claim limitation is a means-plus-function limitation, two steps of claim construction remain: 1) the court must first identify the function of the limitation; and 2) the court must then look to the specification and identify the corresponding structure for that function. Med. Instrumentation, 344 F.3d 1205 at 1210. If there is no structure in the specification corresponding to the means-plus-function limitation in the claims, the claim will be found invalid as indefinite. See Atmel, 198 F.3d at 1378-79 (citing In re Donaldson, 16 F.3d at 1195).

The court did throw patentees a bone stating that:

While the specification must contain structure linked to claimed means, this is not a high bar: “[a]ll one needs to do in order to obtain the benefit of [§ 112, 6] is to recite some structure corresponding to the means in the specification, as the statute states, so that one can readily ascertain what the claim means and comply with the particularity requirement of [§ 112,] 2.” Atmel, 198 F.3d at 1382. Additionally, interpretation of what is disclosed in the specification must be made in light of the knowledge of one skilled in the art. Id. at 1380.

See the entire opinion here: Biomedino CAFC Opinion

Posted June 20th, 2007 by Stephen Albainy-Jenei in IP Litigation
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Jim Harlan, Patent Counsel at Siemens Automation and Drives, UGS PLM Software (and former Blawger Bowl III competitor), has gone wild and started a new patent blog, Patents Gone Wild. The site features Jim’s thoughts/musings on the business impact patents play as an intangible asset.

One recent post asks about the ramifications of the Indian Patent Act, which requires that anyone (including corporations) resident in India who wish to file a patent abroad, say the US, must first obtain a foreign filing license from the Indian Government.

Jim asks:

What does that mean for a US Corp that utilizes developers in India, where those developers are potentially inventors?

Does this include Provisional Applications?

In the US, the inventors are the applicants, but in India the Corp is the applicant. What effect does that have on the process?

I would be interested in hearing the opinions of patent practitioners in India on these questions.

Update on 09/19/07:

Due to a cease and desist letter from a certain company using the words “Gone Wild” in their name, Jim has moved Patents Gone Wild to a new site:  Feral Patents 

Posted June 20th, 2007 by Stephen Albainy-Jenei in Blawg Reviews
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After refusing to die easy on its bid to put out a generic version of Plavix, Apotex was handed its hat by the district court. Sanofi-Synthelabo v. Apotex Inc., 02cv2255, U.S. District Court, Southern District of New York.

Granting a permanent injunction, U.S. District Judge Sidney Stein held that Apotex failed to prove by clear and convincing evidence that the Sanofi-Synthelabo patent on Plavix — U.S. Pat. 4,847,265 — is invalid or unenforceable on any of the grounds asserted.

Plavix® (clopidogrel bisulfate) is a platelet aggregation inhibiting agent used to reduce thrombotic events such as heart attacks and strokes. The active ingredient in Plavix® is the bisulfate salt of the d-enantiomer of the free base methyl alpha-5-(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)-(2-chlorophenyl) acetate (MATTPCA), which is specifically recited in claim 3 of the ’265 patent.

Apotex had filed an Abbreviated New Drug Application (”ANDA”) pursuant to the Hatch-Waxman Act seeking FDA approval to manufacture and sell a generic version of clopidogrel bisulfate. When Apotex filed a Paragraph IV certification with its ANDA asserting that the ‘265 patent is invalid, Sanofi sued Apotex on the ‘265 patent.

The parties had negotiated a settlement agreement that provided for actions in the event that the settlement failed to receive regulatory approval. But, after state attorneys general said they would not approve the settlement, litigation resumed.

Pursuant to the agreement, Apotex launched its generic clopidogrel bisulfate product on and Sanofi filed for a preliminary injunction and requested a recall of Apotex’s products that were already distributed. The district court granted the motion for injunctive relief but denied the request for recall even though Apotex had already shipped a six-month supply of its product to distributors in the US.

Apotex counterclaimed, asserting that the ‘265 patent was invalid for three separate reasons and unenforceable as well:

1. That the ‘265 patent is anticipated pursuant to 35 U.S.C. § 102(b) by an earlier patent held by Sanofi that covered a genus of chemical compounds called thienopyridines, within which clopidogrel bisulfate falls.
2. That pursuant to 35 U.S.C. § 103, the subject matter claimed in the ‘265 patent would have been obvious to a person of ordinary skill in the art at the time the invention was made.
3. That the patent is invalid under the judicial doctrine of obviousness-type double patenting.
4. That the ‘265 patent is unenforceable on the basis of Sanofi’s alleged inequitable conduct before the U.S. Patent and Trademark Office, i.e., failing to name Dr. Jean-Pierre Maffrand as an inventor, making false statements to the PTO regarding the unexpected pharmacological properties of clopidogrel bisulfate, failing to disclose relevant prior research that Sanofi had conducted on a similar chemical compound, and failing to disclose a journal article that Apotex alleges is a material prior art reference.

The court came down hard on Apotex and let them know that none of these assertions would fly. In its findings, the court stated:

Having conceded infringement, Apotex bears the burden of proof because “[a] patent shall be presumed valid,” and “[t]he burden of establishing invalidity of a patent or any claim thereof shall rest on the party asserting such invalidity.” 35 U.S.C. § 282. To overcome this presumption of validity at trial, “the party challenging a patent must prove facts supporting a determination of invalidity by clear and convincing evidence.”

The court noted that this is a “heavy burden,” … because clear and convincing evidence “proves in the mind of the trier of fact ‘an abiding conviction that the truth of [the] factual contentions [is] highly probable.’” The burden of showing invalidity is “especially difficult” when “the infringer attempts to rely on prior art that was before the patent examiner during prosecution.” … Here, not only was the prior art patent – the ‘596 patent – before the patent examiner during the prosecution of the ‘265 patent, but also the very same patent examiner, Bernard Dentz, approved both the ‘596 patent and the ‘265 patent.

In its decision affirming this Court’s grant of a preliminary injunction in favor of Sanofi, the Federal Circuit found that “the plain language of claim 2 [of the ‘596 patent] only recites the free base, MATTPCA, and does not expressly describe the dextrorotatory or levorotatory enantiomers or any salt. Because claim 2 [of the ‘596 patent] fails to describe each and every limitation of claim 3 [of the ‘265 patent] on its face, claim 2 does not anticipate claim 3.” Sanofi-Synthelabo v. Apotex, Inc., 470 F.3d 1368, 1376 (Fed. Cir. 2006), reh’g denied, 2007 U.S. App. LEXIS 2807 (Fed. Cir. Jan. 19, 2007). Nothing in the trial record changes the plain language of the patents, and this Court therefore reaches the same conclusion on a complete record as this Court and the Federal Circuit reached on a more limited record: Claim 2 of the ‘596 patent does not expressly describe clopidogrel or its bisulfate salt. The Court also finds that Example 1 does not expressly describe clopidogrel bisulfate – there is no explicit reference to the enantiomers of PCR 4099 in that example and the particular salt described is the hydrocholoride, not the bisulfate.

The more difficult question is whether the additional limitations – namely the dextrorotatory enantiomer and its bisulfate salt – are inherently described elsewhere in the ‘596 patent. “Inherent anticipation requires that the ‘missing characteristic is necessarily present, or inherent, in the single anticipating reference.’”

Claim 1 of the ‘596 patent claims a general formula and specifies that the compounds covered by that formula include: their addition salts with pharmaceutically acceptable mineral or organic acids . . . including both enantiomeric forms or their mixture. ‘596 patent at col. 13, ll. 8-19. The parties have stipulated that clopidogrel bisulfate is a compound within the genus of Claim 1 of the ‘596 patent.

Claim 8, which is also relevant, reads as follows: A therapeutic composition having blood-platelet aggregation inhibiting activities and anti-thrombotic activities containing an effective amount of a compound of claim 1, or an addition salt thereof with a pharmaceutically acceptable mineral or organic acid or with mineral bases, or one of the two enantiomers or their mixture and a pharmaceutically acceptable carrier.

In the end, the court held that:

Apotex’s argument, however, is ultimately unpersuasive. First, it is undisputed that “[a] prior art reference that discloses a genus still does not inherently disclose all species within that broad category.” Metabolite Labs., Inc. v. Lab. Corp. of Am. Holdings, 370 F.3d 1354, 1367 (Fed. Cir. 2004); see also Atofina, 441 F.3d at 999. In essence, patentability is not precluded by the fact that an inventor has identified or selected a single compound with particularly desirable qualities from a large class of previously patented compounds.

Although clopidogrel bisulfate concededly falls into the broad genus disclosed by Claims 1 and 8 – a genus which includes millions of possible compounds – a person of ordinary skill in the art would need to engage in impermissible “mechanistic dissection and recombination” of those disparate elements to arrive at the particular combination that is clopidogrel bisulfate.

The Court also refused to buy Apotex’ argument that clopidogrel bisulfate was rendered obvious by the ‘596 patent because, after gaining familiarity with that patent, a person of ordinary skill in the art would have viewed as obvious the active enantiomer of PCR 4099 in the form of each of the three salts used for ester compounds in the examples of the ‘596 patent – namely, the hydrochloride, bisulfate and hydrobromide.

Apotex tried arguing that the results were not unexpected and urged that the recent decision of the Federal Circuit, Pfizer, Inc. v. Apotex, 480 F.3d 1348 (Fed. Cir. 2007), would yield a different conclusion in this case. The Court, however, distinguished the present case from Pfizer since after obtaining that patent, Pfizer discovered that the maleate salt, for unforeseen reasons, was not suitable for the commercial manufacture of tablets due to stickiness and tablet degradation. The chemists at Pfizer attributed those problems to the particular chemical structure of the maleate salt – a reactive double bond in the maleate anion – which made the salt susceptible to degradation. In this case, there were no structural features that would have guided selecting any specific acid.

While Apotex will surely file an appeal with the federal circuit, it doesn’t seem likely that the outcome will change. The federal circuit already found a “a reasonable likelihood of its success on the merits” in favoring issuance of a preliminary injunction.

See the full opinion here:  Sanofi v. Apotex Opinion

Posted June 19th, 2007 by Stephen Albainy-Jenei in IP Litigation
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