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 .
DETAILED ACTION
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 49, and 51-60 have an effective filing date of 11 MAR 2016.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/14/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of Claims
Claims 49, and 51-60 are currently pending and presented for examination on the merits.
Claims 49, 51, and 56-57 are amended.
Claim 60 is new.
Claims 1-48, and 50 are canceled.
Rejections Withdrawn
The rejection filed under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claims.
The rejection filed under Double Patenting is withdrawn in view of Applicant’s amendments to claims.
Rejections Maintained
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 49, 51-60 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.
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. Regarding the elected species, the instant specification discloses an antagonist antibody that binds proTGFB1, but not to proTGFB2 or proTGFB3, inhibits LRRC33-mediated TGFB1 activity and/or LRRC33-proTGFB1 cell surface expression in tumor-associated macrophages (TAMs), and inhibition of tumor growth or reduction of tumor volume comprising SEQ ID NOs: 95 and 97. However, the specification does not adequately disclose, for example, a genus of antibodies that specifically binds to proTGFB1, but not to proTGFB2 or proTGFB3, inhibits LRRC33-mediated TGFB1 activity and/or LRRC33-proTGFB1 cell surface expression in tumor-associated macrophages (TAMs), and inhibition of tumor growth or reduction of tumor volume.
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.
MacCallum et al. (Journal of Molecular Biology, 1996, 262:732-745) analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominates, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right column) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left column). 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). Chen et al. (Journal of Molecular Biology, 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). There is insufficient evidence or nexus that would lead the skilled artisan to predict the ability of an antibody to bind proTGFB1, but not to proTGFB2 or proTGFB3, inhibits LRRC33-mediated TGFB1 activity and/or LRRC33-proTGFB1 cell surface expression in tumor-associated macrophages (TAMs), and inhibition of tumor growth or reduction of tumor volume.
Furthermore Applicant has not disclosed relevant, identifying characteristics of CDR region amino acid sequences (or combinations thereof) that confer upon an antibody the ability to a) reduce the number of TAMs and/or myeloid-derived suppressor cells (MDSCs) in the solid tumor (claim 56), or b) increase the ratio of M1 over M2 macrophages in the solid tumor (claims 57), because the instant specification does not provide structural antibody features that correlate with a functional ability to a) reduce the number of TAMs and/or myeloid-derived suppressor cells (MDSCs) in the solid tumor (claim 56), or b) increase the ratio of M1 over M2 macrophages in the solid tumor (claims 57). Absent a description of the at least minimal structural features correlating with a functional ability to a) reduce the number of TAMs and/or myeloid-derived suppressor cells (MDSCs) in the solid tumor (claim 56), or b) increase the ratio of M1 over M2 macrophages in the solid tumor (claims 57) which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which heavy and light chain CDR amino acid sequences (or combinations thereof) may be combined such that the resultant heavy and light chain variable regions comprise six CDRs that confer upon an antibody the ability to a) reduce the number of TAMs and/or myeloid-derived suppressor cells (MDSCs) in the solid tumor (claim 56), or b) increase the ratio of M1 over M2 macrophages in the solid tumor (claims 57).
Although screening techniques can be used to isolate CDR variant antibodies that possess the ability to bind proTGFB1, but not to proTGFB2 or proTGFB3, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also 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.”
With respect to claim 60, this claim lacks adequate written description, at least because absent empirical determination, one skilled in the art would be unable to readily envision an anti-TGFβ1 antibody that does not bind free mature TGFβ1 that is not associated with a pro/latent complex.
Accordingly given the unpredictability associated with antibody CDR region changes on antigen binding and given the lack of particularity with which the claimed antibodies are described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the specification would not reasonably convey to the skilled artisan that Applicant was in possession of the claimed invention at the time the application was filed.
Applicant’s Arguments:
Applicant respectfully disagrees
The Office's reasoning appears to misapply the case law applicable to composition of matter claims-particularly those directed to antibody sequences- whereas the claims here are directed to methods of identifying a subgroup of antibodies or antigen-binding fragments thereof with anti-tumor activity that bind proTGF31, but not proTGF32 or proTGF33.
Step (a): Provide an isoform-specific anti-proTGF31 antibody or antigen-binding fragment thereof (see, e.g., as-filed specification, [63], Table 5, FIGs. 4A-4B, Example 1);
Step (b): Assess inhibition of LRRC33-mediated activity (see, e.g., id., [453]- [454], [463], [467]-[476], [483], FIGs. 7B and 7E, Examples 4, 5, and 9); and
Step (c): Evaluate anti-tumor activity (see, e.g., id., [75], [485]-[496], FIG. 16, Examples 11 and 12).
Examiner’s Response:
Applicant states, “The Office's reasoning appears to misapply the case law applicable to composition of matter claims-particularly those directed to antibody sequences- whereas the claims here are directed to methods of identifying a subgroup of antibodies or antigen-binding fragments thereof with anti-tumor activity that bind proTGF31, but not proTGF32 or proTGF33.”
MPEP 2163 – II, 3a
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that inventor was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that "if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function".). "Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function." Id.
For some biomolecules, examples of identifying characteristics include a sequence, structure, binding affinity, binding specificity, molecular weight, and length. Although structural formulas provide a convenient method of demonstrating possession of specific molecules, other identifying characteristics or combinations of characteristics may demonstrate the requisite possession. As explained by the Federal Circuit, "(1) examples are not necessary to support the adequacy of a written description; (2) the written description standard may be met … even where actual reduction to practice of an invention is absent; and (3) there is no per se rule that an adequate written description of an invention that involves a biological macromolecule must contain a recitation of known structure." Falkner v. Inglis, 448 F.3d 1357, 1366, 79 USPQ2d 1001, 1007 (Fed. Cir. 2006); see also Capon v. Eshhar, 418 F.3d at 1358, 76 USPQ2d at 1084 ("The Board erred in holding that the specifications do not meet the written description requirement because they do not reiterate the structure or formula or chemical name for the nucleotide sequences of the claimed chimeric genes" where the genes were novel combinations of known DNA segments.). However, the claimed invention itself must be adequately described in the written disclosure and/or the drawings. For example, disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties).
Applicant has not provided the examples of identifying characteristics to include a sequence, structure, binding affinity, binding specificity, molecular weight, and length. To satisfy the written description requirement applicant must describe the complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.
In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 285 (CCPA 1973) (the phrase "air or other gas which is inert to the liquid" was sufficient to support a claim to "inert fluid media" because the description of the properties and functions of the air or other gas segmentizing medium would suggest to a person skilled in the art that appellant’s invention includes the use of "inert fluid" broadly.). See Juno, 10 F.4th 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) (where the claims are directed to species that bind to various selected targets, it is not fatal that all species are not disclosed as long as the patent provides other means of identifying which species would possess the claimed common structural characteristics or shared traits).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DENNIS JOHN SULLIVAN whose telephone number is (571)272-0509. The examiner can normally be reached Mon - Fri: 7:30AM - 4:30PM.
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/DENNIS J SULLIVAN/Examiner, Art Unit 1642
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642