Relating to the drug Lyrica, the CAFC decision in Pfizer v. Teva
has some interesting statements about enablement and written description in the context of having patent coverage on a separated enantiomer with a disclosure of only the racemate.
The appellants (Teva, et al.) argued that merely obtaining the racemate, without teaching "how" to isolate the enantiomer did not satisfy enablement under 35 USC 112:
Appellants also contend that the ’692 application provides nothing more than boilerplate language pointing to unspecified prior art as the basis for making the claimed invention, and fails to disclose the required starting materials, reaction conditions, and other working examples.
However, the CAFC found that making the racemate (not the resolved enantiomer) was enough:
First, there is no requirement that a specification must “disclose what is routine and well known in the art.” Genentech, Inc. v. Novo Nordisk A/S, 108 F.3d 1361, 1366 (Fed. Cir. 1997). Second, as the district court found, there is no dispute in the record that the co-inventors of the ’819 patent were the first to create and claim the chemical compound 3-isobutylGABA. District Court Opinion, at 689. It is also undisputed that the parent application discloses the method for synthesizing the compound and states that the compound’s “enantiomers may be prepared or isolated by methods already well known in the art.” J.A. 3012-14. The district court found support for this fact in the prior art, the prosecution history, and witness- es’ trial testimonies. See District Court Opinion, at 683- 87; see also J.A. 3012-14, 21196-203, 21168-69, 21172-80, 20622-24, 21205-06. The court also acknowledged that the same conclusion was reached by the PTO Examiner, who withdrew an enablement rejection on that very basis during prosecution of the patent. District Court Opinion, at 689 n.41.
Second, according to Sun, despite the patentee describing the separation of the racemate (i.e., isolation of the enan- tiomers) as anything but routine in later applications, at the time of the ’692 application, both inventors readily admitted that they had not yet separated the racemic mixture to obtain a purified enantiomer. See J.A. 20814- 18.
Within the Pfizer v. Teva decision, one will not find a reference to SANOFI SYNTHELABO v. APOTEX INC (CAFC 2008)
. The result in Pfizer v. Teva is in tension with the result in Sanofi v. Apotex.
The Pfizer court: compound’s “enantiomers may be prepared or isolated [from racemates] by methods already well known in the art.”
The Sanofi court: However, as the witnesses agreed, all of the compounds in the ′596 patent are racemates, and neither the twenty-one specific examples nor any other part of the specification shows their separation into enantiomers. The district court reasoned that a person of ordinary skill in the field of the invention would not have been guided to either the dextrorotatory enantiomer of PCR 4099 or its bisulfate salt.
In the Sanofi case, the patent at issue was United States Patent No. 4,847,265 (the ′265 patent), owned by Sanofi-Synthelabo and related companies, and which covered the pharmaceutical product having the common name clopidogrel bisulfate and the brand name Plavix®. Clopidogrel is the common name of the dextrorotatory enantiomer of methyl alpha-5(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)(2-chlorophenyl)-acetate. The 2008 appeal was focused on the question of patentability of this dextrorotatory isomer in view of its known racemate described in earlier Sanofi patents
, specifically, Sanofi's United States Patent No. 4,529,596 (the ′596 patent) and Canadian Patent No. 1,194,875 (the ′875 patent).
Of relevance to Pfizer v. Teva: In the district court, experts for both sides explained the difficulty of separating enantiomers, for they are identical except for the spatial arrangement at one of the carbon atoms. (...)
The record shows five months of experimentation by Mr. Badorc, and eventually the successful separation using a technique called diastereomeric salt formation. This procedure, which originated with Louis Pasteur, is based on the trial of diverse salt-forming compositions and conditions, in the hope of coming upon a lucky combination of reagents that will preferentially select one of the enantiomers and crystallize from the solution in optically pure form.
An issue before the CAFC in Sanofi was whether synthesis of the racemate anticipated the enantiomer:
Claimed subject matter is “anticipated” when it is not new; that is, when it was previously known. Invalidation on this ground requires that every element and limitation of the claim was previously described in a single prior art reference, either expressly or inherently, so as to place a person of ordinary skill in possession of the invention. See Schering Corp. v. Geneva Pharms., Inc., 339 F.3d 1373, 1379 (Fed.Cir.2003); Continental Can Co. USA v. Monsanto Co., 948 F.2d 1264, 1267-69 (Fed.Cir.1991). An anticipating reference must be enabling; that is, the description must be such that a person of ordinary skill in the field of the invention can practice the subject matter based on the reference, without undue experimentation. See Amgen Inc. v. Hoechst Marion Roussel, Inc., 457 F.3d 1293, 1306-07 (Fed.Cir.2006); Elan Pharms., Inc. v. Mayo Found. for Med. Educ. & Research, 346 F.3d 1051, 1054 (Fed.Cir.2003). Anticipation is a question of fact, and the district court's finding of this issue is reviewed for clear error. See Merck & Co. v. Teva Pharms. USA, Inc., 347 F.3d 1367, 1369 (Fed.Cir.2003). (...)
The court heard expert witnesses for both sides, who agreed that persons of ordinary skill in this field would have known that compounds that contain an asymmetric carbon atom have enantiomers. The [PRIOR ART] ′596 specification states: “These compounds having an asymmetrical carbon may exist in the form of two enantiomers. The invention relates both to each enantiomer and their mixture.” ′596 patent, col. 1, lines 39-41. However, as the witnesses agreed, all of the compounds in the ′596 patent are racemates, and neither the twenty-one specific examples nor any other part of the specification shows their separation into enantiomers. The district court reasoned that a person of ordinary skill in the field of the invention would not have been guided to either the dextrorotatory enantiomer of PCR 4099 or its bisulfate salt.
The patent challenger in Sanofi v. Apotex, which was Apotex, took the position of the patent defender in Pfizer v. Teva: Apotex states that the separation of enantiomers is routine, even if time-consuming or requiring some experimentation, and thus that that the separation need not have been performed or described in the reference. Apotex states that the properties of the enantiomers of PCR 4099 are inherently and necessarily present in its known racemate, such that when the enantiomers are separated the previously observed properties are “immediately recognized” in one or the other enantiomer.
But Apotex LOST.
Apotex thus argues that the dextrorotatory enantiomer of MATTPCA cannot be deemed novel, as a matter of law. However, as the district court recognized, that is not the correct view of the law of anticipation, which requires the specific description as well as enablement of the subject matter at issue. To anticipate, the reference “must not only disclose all elements of the claim within the four corners of the document, but must also disclose those elements ‘arranged as in the claim.’ ” Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359, 1369 (Fed.Cir.2008) (quoting Connell v. Sears, Roebuck & Co., 722 F.2d 1542, 1548 (Fed.Cir.1983)); see also, e.g., In re Arkley, 59 C.C.P.A. 804, 455 F.2d 586, 587 (1972) (“[The] reference must clearly and unequivocally disclose the claimed [invention] or direct those skilled in the art to the [invention] without any need for picking, choosing, and combining various disclosures not directly related to each other by the teachings of the cited reference” (emphasis in original)). (...)
Apotex states that it is irrelevant whether the separation of this specific enantiomer is shown in the references, because a person of ordinary skill in this field would know all of the existing techniques for separating stereoisomers, and would presumptively succeed in this particular separation. Apotex points out that the method that was eventually used by Sanofi was a well-known method, even if it involved some experimentation.
The CAFC noted
The ′596 patent reference states only that “if desired, its enantiomers are separated,” and similarly for the Canadian counterpart. The district court found that these references contain no description of how to separate the enantiomers of PCR 4099, and that “[d]iscovering which method and what combination of variables is required is sufficiently arduous and uncertain as to require undue experimentation, even by one skilled in the relevant art.” Sanofi III, 492 F.Supp.2d at 387. This finding has not been shown to be clearly erroneous.
As to obviousness in Sanofi v. Apotex:
The district court assumed that Apotex had made a prima facie case of obviousness based on the reference patents' disclosure of the PCR 4099 racemate, the statements in the patents concerning enantiomers, and the general knowledge that enantiomers may be separated and may differ from each other in biological properties. Upon consideration of the Graham factors, the court held that the unpredictable and unusual properties of the dextrorotatory enantiomer and the therapeutic advantages thereby provided, weighed in favor of nonobviousness, and that Apotex had not met its burden of establishing otherwise.
However, the experts also agreed that it was not predictable whether such differences, if any, would be weak, moderate, or strong, or how they would be manifested. The experts agreed that no known scientific principle allows prediction of the degree to which stereoisomers will exhibit different levels of therapeutic activity and toxicity. The experts agreed that weak stereoselectivity of biological properties is more common than strong stereoselectivity, and that absolute stereoselectivity is rare. Sanofi witnesses testified as to the research team's belief, based on the earlier separations of two other thienopyridines, that separation of enantiomers was unlikely to be productive.
See the 2008 post on IPBiz
Sanofi prevails on PLAVIX at CAFC: enantiomer patentable over racemate
See also the 2004 post on IPBiz
Enantiomers, racemates, and the chiral switch
More recently, in Canada Sanofi’s Patent for Clopidogrel (PLAVIX) Found Valid and Infringed on Appeal; Apotex’s Appeal on Costs Moot
Of Pfizer v. Teva, Patent Docs has the text
In addition, the court had found that the specification stated that "enantiomers may be prepared or isolated by methods already well known in the art," and that there was sufficient support for this statement based on "the prior art, the prosecution history, and witnesses' trial testimonies." Id. at 12.
The Federal Circuit did not believe that this determination was clearly erroneous, and therefore it affirmed that claim 2 was not invalid for lack of enablement. In response to the Appellants' contention that the specification provides no guidance as to how to purify the two enantiomers, the Federal Circuit stated that "the inventors were not required to provide a detailed recipe for preparing every conceivable permutation of the compound they invented to be entitled to a claim covering that compound." Id.
Within Sanofi v. Apotex, the CAFC had stated:
The district court found that these references contain no description of how to separate the enantiomers of PCR 4099, and that “[d]iscovering which method and what combination of variables is required is sufficiently arduous and uncertain as to require undue experimentation, even by one skilled in the relevant art.” Sanofi III, 492 F.Supp.2d at 387. This finding has not been shown to be clearly erroneous.
Hmmm, opposite conclusions, neither of which is clearly erroneous?? A house divided against itself cannot stand.
Pfizer v. Teva is wrongly decided. To have a valid claim to the enantiomer one must enable possession of the enantiomer. Having the racemate is not the same thing as having the enantiomer. Merely because Pasteur, and others, separated enantiomers does not establish enablement for separating a particular enantiomer from its corresponding racemate.
***Some other points related to Pfizer v. Teva at the district court
On March 1, 2011, the PTO issued a Certification of Correction, correcting the "Related Application Data" field on the '175 Patent to read "Divisional of Ser. No. 08/420,905, filed Apr. 11, 1995." With this correction, the '175 Patent claims priority to the '692 application, filed on November 27, 1990, through the '080, '285, and '905 applications.
Within the district court decision: For the reasons that follow, the court finds that the asserted claims of the '819 Patent and claim 1 of the '175 Patent are entitled to priority filing dates of November 27, 1990.
The Federal Circuit has also instructed that "[i]t is unnecessary to spell out every detail of the invention in the specification" to satisfy the enablement requirement and the patent application does not need to disclose specific examples corresponding to every claimed embodiment. See Falko-Gunter Falkner v. Inglis, 448 F.3d 1357, 1366 (Fed. Cir. 2006). On the contrary, § 112 requires only a "reasonable correlation" between the disclosure and the claims. Invitrogen Corp v. Clontech Labs., Inc., 429 F.3d 1052, 1071 (Fed. Cir. 2005). Importantly, the Federal Circuit has established that an issued patent is presumed valid by statute. See 35 U.S.C. § 282. That presumption can be overcome only by clear and convincing evidence, which is defined as evidence that "proves in the mind of the trier of fact an abiding conviction that the truth of [the] factual contentions [is] highly probable." Intel Corp. v. U.S.Int'l Trade Comm'n, 946 F.2d 821, 830 (Fed. Cir. 1991).
The issue at district court:
The plaintiffs assert that claims 1, 2, and 4 of the '819 Patent are entitled to a priority date of November 27, 1990, the date of U.S. Patent Application No. 07/619,692, the Initial Application that led to the '819 Patent, because the '692 application would have enabled persons of ordinary skill in the art to make S-3-isobutylGABA and its single optical isomers without undue experimentation, by a variety of methods. (D.I. 351 at 3.) Conversely, the defendants challenge that claims l, 2, and 4 of the '819 Patent are entitled only to a priority filing date of May 20, 1992, the date of the first continuation-in-part of the Initial Application, U.S. Patent Application No. 07/886,080, because the '692 application did not enable the S enantiomer of3- isobutylGABA as a single optical isomer. (D.I. 352 at 2; D.!. 349 at 24.)
Some evidence from the defendants
In making this argument, the defendants reject the notion that the R and S enantiomers of
3-isobutylGABA were enabled by the '692 application because they could be "prepared or isolated by methods already well known in the art," as the application stated. (Id.) The defendants' expert, Dr. Davies, testified that, as of November 1990, there were three teclmiques that could be used to attempt to obtain a single enantiomer: (1) classical resolution by making diastereomeric salts or derivatives; (2) chiral chromatography; and (3) chiral synthesis34 (!d. (citing Tr. at 603:23-604:19,612:5-14, 612:22-613:2 (Davies)).) The defendants assert that three highly skilled scientists, all employing each approach, attempted and failed to isolate the S enantiomer of 3-isobutylGABA contemporaneously with the filing of the '692 application and after, such that the '692 application's description that the S enantiomer could be resolved by routine methods known in the art was incorrect and, therefore, not enabled. (Id.)
Specifically, the defendants, rely upon the testimony of their expert, Dr. Davies, to argue that Drs. Andruszkiewicz, Pavia, and, at the outset, Yuen, were unable to make the individual enantiomers of S- and R-3-isobutylGABA or non-racemic mixtures of the two. First, the defendants note that while Dr. Andruszkiewicz was able to separate enantiomers of 3- methylGABA, he failed, after extensive experimentation with classic resolution and PLE, to separate the enantiomers of 3-ethylGABA and did not attempt separation of 3-isobuty!GABA because he believed that the available techniques would not work. (...)
Third, the defendants argue that the work of Dr. Yuen, a chemist who was instmcted by Pfizer to separate 3-isobutylGABA's enantiomers and successfully did so, establishes by clear and convincing evidence that separation of the R and S enantiomers could not be accomplished by routine methods available in the 1990 prior art. Specifically, Dr. Yuen testified that, upon reviewing Dr. Pavia's work, he concluded that the classic resolution and PLE methods would prove ineffective. (...)
Dr. Y uen subsequently obtained S-3- isobutylGABA on September 30, 1991, ten months after the filing of the '692 application. (!d. (citing Tr. at 580:19-581:6 (Yuen); DTX-968A at PFE- LYR- 0097732).) (...)
Thus, the defendants argue, in sum, that the '819 Patent is not entitled to the priority filing date of the '692 application, November 27, 1990, because that application provides no direction, guidance, or working examples concerning how to make individual enantiomers or non-racemic mixtures of 3-isobutylGABA other than to state that "[t]he individual diastereomers or enantiomers may be prepared or isolated by methods already well known in the art." Because, the defendants argue, separation of the R and S enantiomers could not be accomplished by metl1ods already known in the art without "undue experimentation" and required Dr. Yuen's invention, the '692 application is not enabled and the appropriate priority filing date for the '819 Patent is May 20, 1992.
The district court rejected the defendants arguments:
Contrary to the defendants' assertions, where a court, as it has here, construes a claim to cover a chemical compound, the specification is not deficient merely because it does not disclose how to prepare a particular form of that compound.40 See In re Hogan, 559 F.2d 595,
606 (C.C.P.A. 1977) (noting that requiring a specification to disclose how to make each particular form of a compound would "impose an impossible burden on inventors and thus on the patent system" and concluding that "[t]here cannot, in an effective patent system, be such a burden placed on the right to broad claims").
Here, of course, THE effective form is the particular form.