Orange Book Blog

Federal Circuit Confirms that Isolated DNA May Be Patented

Assoc. for Molecular Pathology v. Myriad Genetics, No. 2010-1426 (Fed. Cir. 2011)

    by Nabeela Rasheed

In a decision last Friday, the Federal Circuit confirmed that isolated DNA may be patented.  Judge Lourie brought his considerable chemistry background to bear in writing the court's opinion in a case presenting the question of whether isolated DNA is patent-eligible subject matter.

Myriad appealed a district court decision that held, on summary judgment, that the claims of a number of patents relating to the breast and ovarian cancer genes BRCA1 and BRCA2 were invalid because the gene sequences were products of nature and therefore unpatentable.  The Federal Circuit addressed this question, and it also addressed whether the plethora of plaintiffs had standing to challenge the patents.  The following précis discusses the merits of the patent eligibility of isolated DNA molecules and methods of diagnosis.  The opinion clearly answered the first question in the affirmative for isolated DNA molecules and provided a "maybe" for diagnostic methods, but not in the form presented by Myriad.

In reviewing the patent eligibility of DNA-related claims, the court reverted to the reasoning from the Supreme Court's decision in Chakrobarty, 447 US 1981, the ancestor of most biotechnology decisions in the area of 35 U.S.C. 101.  The test fashioned since that decision focuses on whether a man-made composition is patent-eligible subject matter and answers that it is if the claimed subject matter is a non-naturally occurring composition of matter having a distinct name, character and use.

Applying the test to isolated DNAs, the Federal Circuit concluded here that the challenged claims are drawn to patentable subject matter because the claims cover molecules that are markedly different–-they have distinctive chemical identity and nature--from molecules that exist in nature.  The DNA molecules claimed by Myriad are in an isolated state: they are not the same molecules as those existing in the body.  It took human intervention in cleaving or synthesizing these new chemicals and this human intervention imparts on that isolated DNA a distinctive chemical identify from that possessed by such a chemical within native DNA.

The court took pains to explain that isolated DNA is not merely purified DNA but rather it is a distinct chemical entity defined by separate molecular species joined together by an all-important chemical bond.  In addressing the patent eligibility of the underlying DNA claims, the court dismissed the argument that the DNA should not be patent-eligible because it does not have markedly different characteristics from the characteristics of the DNA in native form.  The court again reiterated that the subject matter is a distinct chemical entity and that focusing on the properties or use of that chemical entity improperly conflates the patent eligibility inquiry with an obviousness inquiry.

In the same vein, the Federal Circuit dismissed the middle-ground arguments advanced by the Patent Office: that isolated DNAs should not be patentable because they can be seen using a "magic microscope" whereas cDNAs cannot.  The court rejected the Patent Office’s argument as it fails to understand the difference between science and invention and fails to recognize that the DNA molecules are separate chemical entities regardless of whether they are cDNA molecules or isolated genomic DNA molecules.  The court noted that the ability to visualize a DNA molecule is "worlds apart" from possession of an isolated DNA.  Noting that this is the difference between knowledge of nature and a reduction of that knowledge to a concrete form, the latter activity being the very ingenuity that the patent laws seek to encourage through protection, the court provided its imprimatur to DNA composition-of-matter claims regardless of whether they are cDNA claims or isolated genomic DNA claims.

The court was not so forthcoming with the same endorsement for the diagnostic method claims as presented in the patents.  All but one of the method claims at issue covered "analyzing" or "comparing" a patient's DNA sequence with the DNA sequence from wild-type or normal patients that do not have cancer to effectively correlate a difference in the DNAs with a cancer.  The court noted that the "analyzing" or "comparing" step is the entire process claimed, and can in fact be a mental step without being tied to some additional transformative test--and hence these method claims fail the test of patent eligibility.  However, that is not to say that Myriad provides the death knell for diagnostic method claims.  Rather, the court stated that "isolating genes to provide useful diagnostic tools and medicines is surely what the patent laws are intended to encourage and protect."

With the above encouragement in mind, it is still possible to obtain claims to methods of diagnosis of a disease as long as the diagnostic methods that involve analysis or comparison of a diseased state with a wild-type or normal state are crafted to include a physical step such as "extraction" or other manipulation of the underlying chemical to be analyzed or compared in the diagnostic step.  Crafting the appropriate language for this additional element in diagnostic method claims will become ever more important with the dawning of the age of personalized medicine and the need for protection of underlying intellectual property focused on personalized medicine.

The court seems to have applied well-established law under 35 U.S.C. 101, including the recent guidance provided by the Supreme Court in Bilski, making it a more remote possibility that the Supreme Court would accept the case review.

Federal Circuit Affirms Summary Judgment of No DOE Infringement in CENESTIN Case

Duramed Pharms., Inc. v. Paddock Labs., Inc., No. 2010-1419 (Fed. Cir. 2011)

    by Scott P. McBride

CENESTIN is a conjugated estrogen pharmaceutical composition used to reduce the symptoms of menopause.  In a 3-0 decision last week, the Federal Circuit affirmed that Paddock's generic version of CENESTIN would not infringe U.S. Patent No. 5,908,638, directed to conjugated estrogen compositions, under the Doctrine of Equivalents.

Claim 1 of the '638 patent recites:

A pharmaceutical composition in a solid, unit dosage form capable of oral administration for the hormonal treatment of peri-menopausal, menopausal and post-menopausal disorders in a woman comprising: conjugated estrogens coated onto one or more organic excipients forming a powdered conjugated estrogen composition where said composition is substantially free of inorganic excipients and further comprises about 30-70% gel-forming organic excipient and about 30-70% non-gel forming organic excipient by weight and having less than about 2.5% free water by weight and greater than 2.5% total water wherein said solid unit dosage form is coated with a moisture barrier coating comprising ethylcellulose.

In 2008, Paddock filed an ANDA for a generic version of CENESTIN, after which Duramed filed suit for infringement of the '638 patent.  Duramed asserted infringement of independent claim 1 and dependent claims 4 and 6-8 under the doctrine of equivalents only.

In an opinion last year, District Judge Sand (S.D.N.Y.) concluded on summary judgment that the four asserted claims were not infringed under the doctrine of equivalents due to prosecution history estoppel.  During prosecution, claim 1 originally recited a conjugated estrogen pharmaceutical composition "coated with a moisture barrier coating" (MBC).  Original dependent claim 7 limited "said moisture barrier coating" to one that "comprises ethylcellulose."  After initially rejecting both claims as obvious, the examiner later advised that he would allow the application if Duramed amended claim 1 to include the limitations of claim 7.  In response, Duramed amended claim 1 to recite pharmaceutical compositions with "a moisture barrier coating comprising ethylcellulose."

Judge Sand concluded that the amendment adding the ethylcellulose limitation was substantially related to patentability and narrowed the claim scope, thus triggering the Festo presumption that Duramed had surrendered all territory between the original and amended claim scope (i.e., between "coated with a moisture barrier coating" and coated with a moisture barrier coating "comprising ethylcellulose").  Judge Sand also concluded that Duramed had failed to rebut the Festo presumption based on an argument of the unforeseeability of the use of polyvinyl alcohol (PVA) MBC, used in Paddock's proposed generic product and marketed as Opadry AMB.  Judge Sand concluded that PVA MBCs were foreseeable at the time of Duramed's narrowing amendment (December 1998) because, among other things: (1) a Colorcon PCT application published in January 1996 described PVA as "a moisture barrier coating for pharmaceutical tablets and the like"; (2) pre-September 1996 invoices existed for the sale (by Colorcon) of Opadry AMB; and (3) a 1976 patent to Groppenbächer disclosed the use of PVA in moisture-tight tablets.

In affirming, the Federal Circuit noted that Duramed could rebut the presumption of prosecution history estoppel by showing that the alleged equivalent would have been unforeseeable at the time of the amendment and was thus beyond a fair interpretation of what was surrendered.  Duramed argued that the district court applied the wrong legal test for foreseeability, and that an equivalent is not foreseeable unless it was understood by one of ordinary skill to be suitable for use in the invention as originally claimed.  But the Federal Circuit rejected Duramed's arguments.

Duramed argued that foreseeability requires that PVA must have been known as an MBC for moisture-sensitive pharmaceutical compounds, like the claimed conjugated estrogens.  Relying on Schwarz Pharma, Inc. v. Paddock Labs., Inc., 504 F.3d 1371, 1377 (Fed. Cir. 2007), the Federal Circuit stated that when the language of the original and issued claims begins with the words "[a] pharmaceutical composition," that language (and not merely the specifically-claimed constituent ingredient (here, conjugated estrogens)) defines the field of the invention for purposes of determining foreseeability.  Accordingly, PVA MBCs need only to have been known in the field of pharmaceutical compositions, as of the time of Duramed's narrowing amendment.  Because the Colorcon PCT discloses PVA MBCs, including Opadry AMB, in the field of pharmaceutical compositions, such PVA MBCs were "known in the field of the invention," and thus foreseeable.  Thus, the Federal Circuit held that the Colorcon PCT established foreseeability as a matter of law.

The Federal Circuit also explained that "foreseeability does not require . . . precise evidence of suitability.  . . .  Foreseeability does not require flawless perfection to create an estoppel."  Thus, the Federal Circuit rejected Duramed's arguments that the Colorcon PCT did not establish foreseeability due to its inclusion of (1) technical drawbacks, and (2) conclusory statements, rather than test data showing precise characteristics or precise suitability.

Finally, the Federal Circuit held that no genuine issue of fact precluded a finding that a December 1995 article in the scientific journal "Manufacturing Chemist" was publicly available to assess foreseeability.  In reaching this conclusion, the Federal Circuit emphasized that the amendment date (December 1998), not the application date (July 1995), was the pertinent time for determining foreseeability.

Federal Circuit Affirms Summary Judgment of Invalidity for Obviousness in Temazepam Case

Tyco Healthcare Group LP v. Mutual Pharm. Co., No. 2010-1513 (Fed. Cir. 2011)

   by Scott P. McBride

RESTORIL (temazepam) is a hypnotic (sleep-inducing) drug marketed for the treatment of insomnia.  In a decision last month, the Federal Circuit affirmed the invalidity of two claims of U.S. Patent No. 5,211,954 directed to temazepam formulations.  Claim 1 recites:

A hard gelatin capsule containing a temazepam formulation consisting essentially of 6 to 8 milligrams of crystalline temazepam having a surface area of from 0.65 to 1.1 m2/g and 95% of the temazepam having a particle size of less than 65 microns in admixture with a pharmaceutically acceptable carrier therefor.

Claim 2 "is identical except that it recites a composition containing 7.5 milligrams of crystalline temazepam."

In 2006, Mutual filed an ANDA for a generic version of 7.5 mg temazepam capsules, after which Tyco filed suit for infringement of the '954 patent.  In 2009, after Mutual received tentative FDA approval of its ANDA, Tyco moved for a preliminary injunction, which was denied due to "uncontroverted evidence" of no literal infringement due to the "surface area" limitation.

In an opinion last year, District Judge Chesler (D.N.J.) concluded on summary judgment that the two asserted composition claims were invalid for obviousness.  Judge Chesler noted that (1) RESTORIL capsules had been sold in the United States in 15 mg and 30 mg dosages more than a year before the 1986 priority date of the '954 patent, (2) a 1983 volume of the British National Formulary, a UK medical reference book, directed physicians to the use of temazepam at a dosage between 5 and 15 mg for the treatment of insomnia in the elderly, and (3) it was undisputed that "physicians always seek to prescribe the lowest effective dose of any medication, particularly hypnotics such as temazepam."

In affirming, the Federal Circuit noted that, when Tyco's predecessor filed a Supplemental NDA with the FDA for manufacture and sale of 7.5 mg temazepam capsules within the scope of both '954 claims, the application stated that:

[t]he formulation and manufacture of RESTORIL Capsules, 7.5 mg are similar to that used for the 15 and 30 milligram capsules . . . .  The [7.5 mg] formulation differs only in the reduction of the dose.  . . .  The capsule manufacturing method is exactly the same as has been described for the currently marketed doses.

The Federal Circuit stated, "[g]iven that uncontested description, the only limitation of the two '954 claims that was not fully disclosed by the prior art RESTORIL capsules is the lower dosage of temazepam."

The district court and the Federal Circuit relied on, among other things, the 1983 British National Formulary book.  The British National Formulary book stated that, for temazepam, the dose for "elderly patients [could be] 5-15 mg."  According to the district court, "[t]his entry plainly tells one of skill in the art to treat insomnia in the elderly by administering a dose in the range of 5 to 15 mg."  Moreover, the summary judgment record included evidence of a 1984 statement by an FDA representative to a group that included the named inventor of the 954 patent, that "the doses proposed in [certain] studies may be too high, [given] that in Great Britain, temazepam doses from 5-15 mg are recommended for geriatrics."

The Federal Circuit stated that where there is a range disclosed in the prior art, and the claimed invention falls within that range, the claim is presumed obvious.  That presumption is rebuttable either by a showing that the prior art taught away from the invention or by a showing of new and unexpected results. 

The Federal Circuit did not accept Tyco's arguments that the prior art taught away from the claimed invention or that secondary considerations of new and unexpected results and commercial success permitted a conclusion of non-obviousness.  The Federal Circuit also rejected, as "silly," one assertion made by Tyco's counsel at oral argument that the language "5-15 mg" did not actually disclose a range of doses (even though Tyco's expert had called it a "range").

Regarding that same range, the Federal Circuit also concluded that even if some of the references in the record taught away from the claimed dose generally, those teachings did not undermine the teachings in the British National Formulary book that related to the dosage in elderly patients. 

Finally, the Federal Circuit acknowledged, as correct, Tyco's expert's statements that the British National Formulary book (1) "nowhere states that a temazepam dose of 5 mg, 6 to 8 mg, or 7.5 mg, is effective in treating insomnia," (2) nor does it "state that 7.5 mg was effective," and (3) the British National Formulary book provides "[n]o clinical or statistical evidence . . . demonstrating that a dose within a range of 5-15 mg would work" in treating insomnia.  But the Federal Circuit also concluded that these observations do not undermine the district court's conclusions as to obviousness because the 954 patent's composition claims do not discuss the intended use of the capsules in a particular treatment regimen.

Federal Circuit Changes Course, Denies Stay of Injunction of Mylan's Generic AMRIX Sales

In Re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litigation, No. 2011–1399 (Fed. Cir. 2011)

This case has an unusual history.  Here is a brief summary of recent events:

• April 8: U.S. District Court for the District of Delaware enjoins Mylan from launching its generic AMRIX until the court issues its opinion on the patent infringement and validity issues in the case
• April 17: 30–month stay of FDA approval of Mylan's cyclobenzaprine ANDA expires
• April 18: FDA grants final approval of Mylan's ANDA
• May 12: District court issues its opinion (following seven-day bench trial held in September and October of 2010), finding asserted claims of the patents-in-suit invalid for obviousness (link)
• May 13: Mylan launches its generic AMRIX with 180–day exclusivity
• May 20: District court grants Cephalon's motion for a temporary restraining order, explaining that “plaintiffs' success on appeal is just as likely as not” (link)
• May 24: District court issues an Injunction Order, enjoining Mylan's further sales of generic AMRIX; enjoining Cephalon's licensing of an authorized generic version of AMRIX; and ordering Mylan and Cephalon to recall any already-sold generic AMRIX from the market
• May 25: Federal Circuit issues an Order (1) directing Cephalon to file a response to Mylan's motion for a stay, pending appeal, of the district court injunction; and (2) granting “Mylan's request for an immediate stay . . . to the extent that the injunction is temporarily stayed pending the court's receipt of the response and the court's consideration of the papers submitted.”

In an Order issued today, the Federal Circuit granted Mylan's motion for a stay, pending appeal, of the district court's injunction—but only in part.  Citing a 1987 Supreme Court case, the Federal Circuit stated the standard for obtaining a stay:

The party requesting a stay bears the burden of showing that the circumstances justify an exercise of that discretion based on consideration of four factors, the first two of which are the most critical: (1) whether the stay applicant has made a strong showing that he is likely to succeed on the merits; (2) whether the applicant will be irreparably injured absent a stay; (3) whether issuance of the stay will substantially injure the other parties interested in the proceeding; and (4) where the public interest lies.

In view of these factors, the court concluded:

Based on the arguments in the motions papers, and without prejudicing the ultimate disposition of this case by a merits panel, we determine that Mylan has met their burden to obtain a stay, pending appeal, of the district court's injunction in part.  We deem it proper to stay the injunction as to Paragraph 3 of the Injunction Order only.  Mylan's motion to stay the remainder of the injunction provisions is denied.

Paragraph 3 of the Injunction Order directed Mylan and Cephalon to “take all reasonable steps to recall their respective generic cyclobenzaprine extended-release products promptly from the market. . . .”  It is not clear why, if “Mylan has met their burden to obtain a stay,” the Federal Circuit lifted only that part of the injunction requiring Mylan to recall its generic AMRIX from the market, and not also the part ordering Mylan to stop selling its generic AMRIX.

In any event, it appears that Mylan must now stop selling its generic AMRIX.  Presumably Mylan has been selling its generic AMRIX since it launched on May 13, meaning that it has received the benefit of 56 days of its 180–day exclusivity period.  Due to the Federal Circuit's calendar for oral argument, however, the appeal won't be heard until September at the earliest.  Meanwhile, Mylan's 180–day exclusivity period will continue to run.  Thus, it is unclear whether, even if Mylan prevails on appeal, it will have any exclusivity remaining by the time the Federal Circuit issues its opinion in the case.

Federal Circuit Allows Par's Appeal of ASACOL Declaratory Judgment Decision to Proceed

Medeva Pharma Suisse v. Par Pharmaceutical, No. 2011–1391 (Fed. Cir. 2011)

In an Order issued today, the Federal Circuit denied Medeva's motion to dismiss Par's appeal of a decision from the U.S. District Court for the District of New Jersey that dismissed Par's declaratory judgment claim in paragraph IV litigation involving ASACOL (mesalamine).  Medeva had filed suit against Par for infringement of only one of two Orange Book-listed patents.  Par counterclaimed for a declaratory judgment of invalidity as to the other patent, seeking to trigger forfeiture of the first ANDA filer's 180–day exclusivity.  Medeva then offered a covenant not to sue, after which the district court dismissed Par's declaratory judgment claim.  Click here for FDA Law Blog's excellent summary of the district court's decision.

After dismissing Par's declaratory judgment claim, the district court entered judgment under Rule 54(b), allowing Par immediately to appeal the decision.  According to the district court, if the decision were to be reversed on appeal, then the court could possibly try the claims on both patents at the same time, because the issues involving the first patent were still in discovery.

Rule 54(b) permits a district court “to direct the entry of a final judgment as to one or more but fewer than all of the claims or parties only upon an express determination that there is no just reason for delay and upon an express direction for the entry of judgment.”  In today's Order, the Federal Circuit stated that its task was “only to assess whether the movant can establish the district court abused its discretion in finding the final claim should be heard now as opposed to waiting until all claims against all parties have been entered.”  The court concluded:

Medeva cannot meet this standard.  The trial court appears to have considered both parties' arguments, and provided a thorough explanation for why judicial resources could be conserved if judgment was entered pursuant to Rule 54(b).  Because the court cannot say the district court abused its discretion, we deny the motion to dismiss.

Accordingly, Par's appeal will go forward, and the Federal Circuit will consider whether the district court properly dismissed Par's declaratory judgment claim against Medeva.