DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restriction
The response filed on 7/17/26 to the restriction requirement of 7/1/26 has been received. Without traverse, Applicant has elected “antibody C952 (i.e., SEQ ID NOs: 133 and 134).”
The elected species is free of the prior art.
Claims 7-17, 19, 20, 27-31, 33, and 34 are pending and are currently under consideration.
Improper Markush
Claims 7-17, 19, 20, 27-31, 33, and 34 are rejected on the basis of claims 7-10 containing improper Markush groupings of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 706.03(y).
The Markush groupings of claims 7-10 are improper because the VH region sequences, VL region sequences, and pairs of VH and VL region sequences described by the Markush grouping are not functionally equivalent and do not share both a single structural similarity and a common use for the following reasons: the sequences and pairs of sequences comprise different sequences derived from different antibodies and have distinct possible uses and distinct possible functions of binding distinct epitopes of SARs-CoV2.
The examiner acknowledges two PTAB decisions that found proper Markush claims: Ex parte Narva (PTAB 2018-006168) and Ex parte Buyyarapu (PTAB Apeal 2018-006665). The grouping of Ex parte Narva is a grouping of a recognized class of polynucleotide sequences (polynucleotides that are hybridized in dsRNA molecules and encode Ras-opposite protein) that share a demonstrated common use (ability to silence Ras-opposite protein). The grouping of Ex parte Buyyarapu is a grouping of five distinct polynucleotides of close proximity to one another within the cotton genome that share a demonstrated common use as markers to screen for a particular type of resistance. In contrast to the polynucleotide sequences of Narva that share a common use (ability to silence Ras-opposite protein) and the polynucleotides of Buyyarapu that share a common use as markers to screen for a particular resistance, the sequences and pairs of sequences of the instant Markush groups do not share a common use. Rather, the sequences and pairs of sequences defined by the instant Markush groups comprise sequences derived from structurally different antibodies and have distinct possible uses of being able to bind distinct epitopes of SARs-CoV-2. The improper Markush grouping of the instant claims is similar to the improper Markush grouping of Appeal 2016-003639, where PTAB found a grouping of 133 polynucleotide sequences that do not share any common sequence do not share a common structure.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 7-9, 11-17, 19, 20, 27-31, 33, and 34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. In the instant case, the claims are inclusive of (i) a genus of anti-SARs-CoV-2 antibodies and antigen-binding fragments thereof comprising three HCDRs of just any heavy chain variable region sequence recited by claim 7 and three LCDRs of just any light chain variable region sequence recited by claim 7 (see claims 7-8); (ii) a genus of products comprising polynucleotides encoding anti-SARs-CoV-2 antibodies and antigen-binding fragments thereof comprising three HCDRs of just any heavy chain variable region sequence recited by claim 7 and three LCDRs of just any light chain variable region sequence recited by claim 7 (see claim 27); and (iii) a genus of anti-SARs-CoV-2 antibodies and antigen-binding fragments thereof comprising just any heavy chain variable region sequence recited by claim 9 and just any light chain variable region sequence recited by claim 9. The specification does not disclose, and the art does not teach, the genus of antibodies and antigen-binding fragments thereof as broadly encompassed in the claims.
Anti-SARs-CoV-2 antibodies and antigen-binding fragments of claims 7-8 are defined as having CDR regions of recited variable heavy and light chains. One of skill in the art would recognize that CDR regions are regions of antibodies that interact with antigen and that there are known ways to “predict” possible CDR sequences from known variable heavy and light chains (Kabat scheme, Chothia scheme, IMGT scheme, etc); however, techniques such as X-ray crystallography are required to definitely determine the CDR regions of a given antibody. In the instant case, the CDR regions of the recited antibodies and binding fragments thereof have not been identified.
Anti-SARs-CoV-2 antibodies and antigen-binding fragments of claims 7-9 encompass antibodies and antigen-binding fragments that have “mix-and-match” sequences from each list of recited variable heavy and light chains. Without demonstrating that sequences of elected heavy chain variable region SEQ ID NO:133, for example, can bind SARs CoV-2 when paired with sequences of a recited variable light chain other than SEQ ID NO:134 one of skill in the art would not predict that the combination of sequences would bind SARs CoV-2.
One of ordinary skill in the art would recognize that the specificity of an antibody is dependent upon the 6 CDR regions and different combinations of CDR sequences greatly alter antigen binding. The instant specification discloses an antagonist antibody of Annexin A1 comprising the following six CDRs: SEQ ID Nos: 2, 14, 54, 84, 97, and 113. However, the specification does not adequately disclose, for example, a genus of antibodies SEQ ID NOs: 2, 54, and just any other sequences.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proceedings of the National Academy of Sciences, 1982, 79:1979-1983). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function.
The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site is underscored by Casset et al. (Biochemical and Biophysical Research Communications, 2003, 307:198-205), which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, other CDRs play an important role in the recognition process (page 199, left column) and this is demonstrated in this work by using all CDRs except CDR L2 and additionally using a framework residue located just before the CDR H3 (see page 202, left column). Holm et al. (Molecular Immunology, 2007:1075-1084) describes the mapping of an anti-cytokeratin antibody and found that in addition to the involvement of the residues in the CDR3 of the heavy chain in antigen binding, a residue in CDR2 of the light chain was also involved (abstract). There is insufficient evidence or nexus that would lead the skilled artisan to predict the ability of an antibody to bind to SARS CoV-2 comprising fewer than 6 CDR regions of an antibody known to bind SARS CoV-2.
The written description only reasonably conveys anti-SARs-CoV-2 antibodies and antigen-binding fragments thereof of claim 10 as members of the genera. A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common to that genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.”
The inventions at issue in Lilly were DNA constructs per se, the holdings of that case is also applicable to claims such as those at issue here. Further, disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product. See Ariad, 598 F.3d at 1354-55 (“Regardless whether the asserted claims recite a compound, Ariad still must describe some way of performing the claimed methods... the specification must demonstrate that Ariad possessed the claimed methods by sufficiently disclosing molecules capable of reducing NF-kB activity so as to ‘satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of the invention that is claimed.’”) (internal citation omitted); see also Univ. of Rochester v. G.D. Searle& Co., Inc., 358 F.3d916,918 (Fed.Cir.2004) (applying the same analysis to assess written description for claims to a “method for selectively inhibiting” a particular enzyme by administering a functionally defined compound, i.e., a “non-steroidal compound that selectively inhibits activity” of the gene product for that enzyme).
The instant specification fails to provide sufficient descriptive information, such as definitive structural features that are common to the genera. That is, the specification provides neither a representative number of antibodies and antigen-binding fragments thereof that encompass the genera nor does it provide a description of structural features that are common to the genera so that one of skill in the art can ‘visualize or recognize’ the members of the genera. “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Further, in view of Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017) and the Office’s February 2018 memo clarifying written description guidance for claims drawn to antibodies, the 2008 Written Description Training Materials are outdated and should not be relied upon as reflecting the current state of law regarding 35 U.S.C. 112. Further, a “newly characterized antigen” test flouts basic legal principles of the written description requirement (Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017)). Adequate written description of a newly characterized antigen alone is not considered adequate written description of a claimed antibody to that newly characterized antigen. Where an antibody binds to an antigen tells one nothing about the structure of any other antibody. Also, see the Board’s decision in Appeal 2017-010877 (claims to “A monoclonal antibody that binds a conformational epitope formed by amino acids 42-66 of SEQ ID NO:1”).
Since the disclosure fails to describe common attributes or characteristics that adequately identify members of the genera, and because the genera are highly variant, the disclosure is insufficient to describe the genera. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genera as broadly claimed.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, even though Applicant may propose methods of screening for possible members of the genera, the skilled artisan cannot envision the detailed chemical structure of the encompassed genera, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolation. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. See Ariad, 94 USPQ2d at 1161; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Claim Rejections - 35 USC § 112
Claims 7-9, 11-17, 19, 20, 27-31, 33, and 34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for making and using anti-SARs Cov-2 antibodies and antigen-binding fragments thereof of instant claim 10 (having defined combinations of variable heavy and variable light chains) and polynucleotides encoding said anti-SARs Cov-2 antibodies and antigen-binding fragments thereof, does not reasonably provide enablement for making and using the genera of anti-SARs Cov-2 antibodies and antigen-binding fragments thereof or polynucleotides encoding the anti-SARs Cov-2 antibodies and antigen-binding fragments thereof broadly encompassed by claims 7-9, 11-17, 19, 20, 27-31, 33, and 34. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in Ex parte Forman, 230 USPQ 546 (BPAI 1986). They include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, the breadth of the claims, and the quantity of experimentation which would be required in order to practice the invention as claimed.
The instant claims are drawn to making and using anti-SARs Cov-2 antibodies and antigen-binding fragments thereof (and polynucleotides encoding said anti-SARs Cov-2 antibodies and antigen-binding fragments thereof) that are not adequately described (see above written description rejection).
This invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology". Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The specification adequately describes anti-SARs Cov-2 antibodies and antigen-binding fragments thereof of instant claim 10 (having defined combinations of variable heavy and variable light chains). The specification does not adequately describe the genera of anti-SARs Cov-2 antibodies and antigen-binding fragments thereof or polynucleotides encoding the anti-SARs Cov-2 antibodies and antigen-binding fragments thereof broadly encompassed by claims 7-9, 11-17, 19, 20, 27-31, 33, and 34. In particular regards to instant claims 7-8, undue experimentation (involving techniques such as X-ray crystallography) would be required to identify the actual CDR sequences of pairs of recited heavy chain and light chain sequences in order to identify and generate claimed anti-SARs Cov-2 antibodies and antigen-binding fragments (and claimed polynucleotides anti-SARs Cov-2 antibodies and antigen-binding fragments thereof). In particular regards to instant claims 7-9, undue experimentation would be required to determine which combinations of recited variable heavy chain and variable light chain sequences (or CDRs thereof) are (or are not) capable of generating anti-SARs Cov-2 antibodies and antigen-binding fragments thereof in order to identify and generate claimed anti-SARs Cov-2 antibodies and antigen-binding fragments (and claimed polynucleotides anti-SARs Cov-2 antibodies and antigen-binding fragments thereof).
One cannot extrapolate the teachings of the specification to the scope of the claims because the claims are broadly drawn to genera of anti-SARs Cov-2 antibodies and antigen-binding fragments thereof and polynucleotides encoding the anti-SARs Cov-2 antibodies and antigen-binding fragments thereof that are not adequately described and Applicant has not enabled the claims because undue experimentation (involving techniques such as X-ray crystallography) would be required to identify the actual CDR sequences of pairs of recited heavy chain and light chain sequences that bind SARs Cov-2 in order to identify and generate claimed anti-SARs Cov-2 antibodies and antigen-binding fragments (and claimed polynucleotides anti-SARs Cov-2 antibodies and antigen-binding fragments thereof). Further, undue experimentation would be required to determine which combinations of recited variable heavy chain and variable light chain sequences (or CDRs thereof) are (or are not) capable of generating anti-SARs Cov-2 antibodies and antigen-binding fragments thereof in order to identify and generate claimed anti-SARs Cov-2 antibodies and antigen-binding fragments (and claimed polynucleotides anti-SARs Cov-2 antibodies and antigen-binding fragments thereof).
Further, similar to claims at issue in Amgen Inc. v Sanofi, the instant specification does not enable the full scope of the claims.
In view of the teachings above and the lack of guidance, workable examples and or exemplification in the specification, it would require undue experimentation by one of skill in the art to determine with any predictability, that the method would function as claimed.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 7-16, 19, 20, 27, and 31 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception(s) (i.e., a law of nature, a natural phenomenon, and/or an abstract idea) without significantly more. The rationale for this determination is explained below:
Claims 7-16, 19, 20, 27, and 31 are directed to natural phenomenon because the claims recite natural phenomenon (“Step 2A prong one”) and the judicial exception(s) is/are not integrated into a practical application (“Step 2A prong two”). The “natural phenomenon” is: recited anti-SARs-Cov-2 antibodies, antigen-binding fragments thereof, and polynucleotide encoding said antibodies. The instant specification acknowledges the claimed anti-SARs-Cov-2 IGG antibodies were derived from B-cells of patients (Example 1, in particular).The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception(s). A claim that focuses on judicial exception(s) can be shown to recite something “significantly more” than the judicial exception(s) by reciting a meaningful limitation beyond the judicial exceptions. However, in the instant case, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements (when considered both individually and as an ordered combination) are limited to the “pharmaceutically acceptable carrier” of claim 19 - which can be merely water of an aqueous environment (“Step 2B”). Recited anti-SARs-Cov-2 antibodies, antigen-binding fragments thereof, and polynucleotide encoding said antibodies are not markedly different than anti-SARs-Cov-2 IGG antibodies, antigen-binding fragments thereof, and polynucleotide encoding said antibodies found in nature.
Conclusion
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/SEAN E AEDER/ Primary Examiner, Art Unit 1642
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