DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment, filed 05/19/2022, has been entered.
Claims 1-16 are pending.
Election/Restrictions
Applicant’s election without traverse of Group II in the reply filed on 09/18/2025 is acknowledged.
Claims 1-10 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claims 11-16 are currently under examination as they read on a composition comprising an antigen binding protein (ABP) that binds to human CELA1.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 11-16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 11 recites the broad recitation, “an antigen binding protein”, and the claim also recites “preferably an isolated monoclonal antibody” which is the narrower statement of the limitation “an antigen binding protein”. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Furthermore, the recitation of “preferably” renders the claims indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. MPEP2173.05(d)
Claim 15 is further indefinite as it depends from claim 11 directed to a composition not an isolated monoclonal antibody. Applicant is invited amend claim 15 to recite “The composition of claim 11, wherein the isolated monoclonal antibody inhibits…”.
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 11-16 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The present claims encompass a genus of anti-CLEA antibodies defined by their binding specificity to any one of residues of CELA1 as recited in claim 11 and required to have the function of inhibiting human lung elastolytic activity. The present claims do NOT satisfy the written description requirement for the claimed genus because the instant disclosure failed to describe 1) a sufficient representative number of species and 2) relevant identifying characteristic i.e., functional characteristics coupled with a known or disclosed correlation between function and structure.
With regard to representative number of species, the instant specification disclosed a number of species of the genus, e.g., AC5, AC7 and KF4 (paragraph 00114). However, the disclosed species are not sufficient to represent the entire genus as claimed.
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). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The “structural features common to the members of the genus” needed for one of skill in the art to 'visualize or recognize' the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural “stepping stone” to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
The size of the claimed antibody genus comprises substantial variations as one of skill in the art is well aware of the high level of polymorphism and complex nature of immunoglobulins. Schroeder et al. taught that through somatic variation, combinatorial rearrangement of individual gene segments and combinatorial association between different L and H chains, the repertoire of antibody diversity can have greater than 1016 different immunoglobulins (J Allergy Clin Immunol 2010, 125:S41-S52).
Moreover, it is well-known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope. For example, Lloyd et al. taught that over hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Therefore, the disclosed species are not representative of the claimed genus encompassing the substantial variation due to the high level of polymorphism of antibodies as exemplified by the above references.
Regarding structure-function correlation, written description can also be satisfied with disclosure of relevant identifying characteristics, i.e., functional characteristics coupled with a known or disclosed correlation between function and structure. While the term “antibody” does impart some structure, the structure that is common to antibodies is generally unrelated to antigen-binding function because antibody CDRs are necessary for binding and they are highly diverse in structure and their sequence does not correlate to binding in a predictable fashion. The subgenus as recited in claim 30 encompasses more than 220,000 possible variants with substitutions in the CDRs. The Applicant does not have possession of all these variants as not all of them will have the binding function as required by the claims.
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs (or hypervariable regions), 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. (Proc Natl Acad Sci USA 1982 Vol 79 page 1979). 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. MacCallum et al. (J. Mol. Biol. 1996 262, 732-745), analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right col) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.). Pascalis et al. (The Journal of Immunology (2002) 169, 3076-3084) demonstrate that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site (see page 3079, right col.). Although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs (see page 3080, left col.). 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. (BBRC 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, clearly other CDRs play an important role in the recognition process (page 199, left col.) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left col.). Vajdos et al. (J. Mol. Biol. (2002) 320, 415-428), additionally state that antigen binding is primarily mediated by the CDRs more highly conserved framework segments which connect the CDRs are mainly involved in supporting the CDR loop conformations and in some cases framework residues also contact antigen (page 416, left col.). Chen et al. (J. Mol. Bio. (1999) 293, 865-881) describe high affinity variant antibodies binding to VEGF wherein the results show that the antigen binding site is almost entirely composed of residues from heavy chain CDRs, CDR-H1, H2, H3 (page 866). Wu et al. (J. Mol. Biol. (1999) 294, 151-162) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.) but certain residues have been identified as important for maintaining conformation. Padlan et al. (PNAS 1989, 86:5938-5942) described the crystal structure of an antibody-lysozyme complex where all 6 CDRs contribute at least one residue to binding and one residue in the framework is also in contact with antigen. In addition, Lamminmaki et al. (JBC 2001, 276:36687-36694) describe the crystal structure of an anti-estradiol antibody in complex with estradiol where, although CDR3 of VH plays a prominent roll, all CDRs in the light chain make direct contact with antigen (even CDR2 of VL, which is rarely directly involved in hapten binding). Recently, studies have shown that changing in CDRs even alter Fc binding to the Fc receptor and pharmacokinetics (Piche-Nicholas et al. MABS 2018, 10:81-94).
Further, as any residue(s) of CELA1 is the target of the claimed antibodies, Applicant has not provided a sufficient written description of an antibody that selectively binds to such variant targets. One of skill in the art would readily appreciate that such antibody would not reasonably be expected to be able to bind CELA1 and still retain the function of inhibiting human lung elastolytic activity. For example, Lederman et al. (Molecular Immunology 28: 1171-1181, 1991; see entire document) disclose that a single amino acid substitution in a common allele ablates binding of a monoclonal antibody. Further, Li et al. (PNAS 77: 3211-3214, 1980; see entire document) disclose that dissociation of immunoreactivity from other biological activities when constructing analogs (see entire document). Therefore, the specification does not provide for sufficient written description to reasonably convey to one skilled in the relevant art that the inventors, at the time the application was filed, had possession of all antibodies binding any one of the residues recited and still have the binding characteristics of the anti-CELA1 antibody capable of inhibiting human lung elastolytic activity encompassed by the claims.
Given the highly diverse nature of antibodies, particularly in the CDRs, by claiming a genus of antibodies defined by the antigen specificity without any defined structure/sequences is analogous to searching for a key “on a ring with a million keys on it” Centocor, 636 F.3d at 1352. Therefore, the claims do not satisfy the written description requirement as the structure-function correlation of the claimed subgenus not sufficiently described.
Given the well-known high level of polymorphism of immunoglobulins / antibodies, the skilled artisan would not have been in possession of the vast repertoire of antibodies and the unlimited number of antibodies encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of antibodies that bind CELA1 having the said functions broadly encompassed by the claimed invention. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “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.) Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
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.)
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 11-16 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Nathan et al. (US 2018/0312477 A1; see entire document).
Nathan et al. disclosed antibodies that bind CELA1 and inhibit CELA1 activity (see, e.g., paragraph 0077). Given that the prior art antibody binds CELA1, it would bind to at least one residue from the recited sequences. Moreover, Nathan taught human monoclonal antibody and scFV (paragraphs 0211 and 0078). Furthermore, Nathan taught a composition comprising a carrier that is sterile and isotonic (paragraphs 0418, 0410, 0409). Given that the prior art antibody inhibits CELA1 activity, it would inhibit human lung elastolytic activity.
Since the Office does not have a laboratory to test the reference antibody, it is Applicant’s burden to show that the prior art antibody does not bind to recited residues or inhibit human lung elastolytic activity.
Conclusion
No claim is allowed.
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/SHARON X WEN/Primary Examiner, Art Unit 1641