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 .
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.
Written Description
Claims 1-8, 11-21, 26, 28, and 30 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.
Claim 1 does not disclose the amino acid sequences of six non-degenerate CDRs for the genus of antibody-based molecules that target human cell migration-inducing and hyaluronan-binding protein (CEMIP). Claim 1 recites only the heavy chain CDRs and thus encompass antibody-based molecules having less than six CDRs required for antigen binding. Further, each heavy chain CDR domain represents a partially defined in which at most 80% of the recited amino acid sequences can vary. The term “antibody-based molecule” also includes single domain antibodies as further evidenced by instant claim 5 that lack six CDRs required for antigen binding by a conventional antibody, including the claimed anti-human CEMIP clones. In addition, claim 1 allows heavy chain CDRs of different anti-human CEMIP antibody clones to be mixed and matched, yet there is no evidence that said antibodies are variants of a single starting clone. With the exception of claims 9 and 10, all claims dependent on claim 1 [or including all of the limitations of claim 1 such as pharmaceutical composition claim 20, nucleic acid claims 17-19, and method claims 21, 28, and 30] fail to cure the deficiencies of claim 1 and are thus also rejected.
Claim 4 (dependent on claim 1) further recites only VH chains and thus encompasses antibody-based molecules having less than six CDRs required for antigen binding. Further, the VH chains represent partially defined structures in which at most 80% of the amino acid sequences can vary in the CDRs and framework regions.
Claim 6 (dependent on claim 1) further recites light chain CDRs that represent partially defined structures in which at most 80% of the recited amino acid sequences can vary. In addition, claim 6 allows for the light chain CDRs of different anti-human CEMIP antibody clones to be mixed and matched; yet there is no evidence that said antibodies are variants of a single starting clone.
Claim 26 does not disclose the amino acid sequences of six non-degenerate CDRs for the genus of anti-CEMIP antibodies or binding fragments thereof that can be used to treat or inhibit brain metastasis in a subject having a primary tumor.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus (MPEP 2163).
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting at 1171, 25 USPQ2d at 1606). Also see (CAFC 2002). Enzo-Biochem v. Gen-Probe Fiers, 984 F.2d 01-1230.
It is well-known in the art that, in order to bind antigen, an antibody or antigen-binding fragment must have six complementarity defining regions (CDRs) (Janeway, see selection, in particular section 3-6) (Janeway, Charles A. "Immunobiology: The Immune System in Health and Disease." 2001). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chain, and not either alone, that determines the final antigen specificity. As presently written, however, claim 1 does not disclose the amino acid sequences of six non-degenerate CDRs for the genus of antibody-based molecules that target human cell migration-inducing and hyaluronan-binding protein (CEMIP) and inhibit CEMIP signaling in order to, for example, block brain metastasis in a subject. Claim 1 recites only the heavy chain CDRs and thus encompass antibody-based molecules having less than six CDRs required for antigen binding. While Applicant has provided examples of anti-human CEMIP antibody-based molecules (see, e.g. Table 5), such disclosure does not adequately represent the structural diversity of the claimed genus of antibody-based molecules that can be used to bind to human CEMIP and inhibit CEMIP signaling in a subject in order to, treat or inhibit brain metastasis. In addition, the term “antibody-based molecule” encompasses single domain antibodies as further evidenced by instant claim 5; however, artisans would not reasonably expect the claimed anti-human CEMIP clones having only a VH domain or a VL domain to be capable of binding to the target antigen since the anti-human CEMIP clones are derived from conventional antibodies having both VH and VL domains.
Further, each heavy chain CDR domain recited in claim 1 represents a partially defined in which at most 80% of the recited amino acid sequences can vary. Such variation can occur, for example, by amino acid substitution, deletion, or insertion. However, there is no guidance provided in the specification about which specific amino acids mutations can made in the heavy chain CDRs of the antibodies or antibody fragments such that the ability of the antibody to bind to human CEMIP and inhibit CEMIP signaling is retained. Indeed, it is well-known that amino acid substitutions in the antibody in the CDR domains can eliminate binding activity (Piche-Nicholas et al, see in particular, Abstract). The level of skill and knowledge in the art is such that one of ordinary skill would not be able to readily identify without further testing which amino acid mutations can be made in the heavy chain CDR sequences such that the ability of the antibodies to bind to human CEMIP and inhibit CEMIP signaling is retained. With the exception of claims 9 and 10, all claims dependent on claim 1 (or including all of the limitations of claim 1) fail to cure the deficiencies of claim 1 and thus are also rejected.
Claim 4 (dependent on claim 1) similarly recites VH chains that represent partially defined structures in which at most 80% of the amino acid sequences can vary in the CDRs and framework regions; yet no guidance is provided about which specific amino acids mutations can made in the CDRs and framework regions of the VH chains such that the ability of the resulting antibody-based molecule to bind to and inhibit human CEMIP is retained.
Claim 6 (dependent on claim 1) similarly recites light chain CDRs that represent partially defined structures in which at most 80% of the recited amino acid sequences can vary, yet no guidance is provided about which specific amino acids mutations can made in the CDRs and framework regions of the VH chains such that the ability of the resulting antibody-based molecule to bind to and inhibit human CEMIP is retained.
Additionally, claims 1 and 6 allow for the heavy chain or light chain CDRs of different anti-human CEMIP antibody clones to be mixed and matched. While the specification teaches the development of several anti-human CEMIP antibody clones, there is no data provided showing that the CDRs from each of the antibody clones can be mixed and matched with each other without substantially impacting the ability of the resulting antibody to bind human CEMIP and inhibit CEMIP signaling as it does not appear that the clones are variants/mutants of a single starting clone. Therefore, artisans could not readily determine which CDRs of different anti-human CEMIP antibody clones can be mixed and matched such that binding affinity for human CEMIP as well as the ability to inhibit CEMIP signaling is maintained commensurate in scope of claim 1.
Lastly, claim 26 does not disclose the amino acid sequences of six non-degenerate CDRs for the genus of anti-CEMIP antibodies or binding fragments thereof that can be used to treat or inhibit brain metastasis in a subject having a primary tumor.
Therefore, the claimed genus of anti-CEMIP antibody-based molecules lacks adequate written description because there does not appear to be any correlation between the structure of the claimed antibody-based molecules and the function of binding to CEMIP and inhibiting CEMIP signaling in order to, for example, treat or inhibit brain metastasis in a subject. Thus, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the claimed genus of anti-CEMIP antibody-based molecules at the time the instant application was filed.
Enablement
Claims 28 and 30 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claims 28 and 30 are broadly drawn to a method of treating inflammatory and autoimmune diseases, respectively, comprising administering a pharmaceutical composition comprising the claimed anti-human CEMIP antibodies.
The specification teaches the development of several anti-human KIAA1199/CEMIP antibody clones, including 10F01B02, 01F11A01, and 07F11C02 (Example 1 and Table 5). It was shown that the CEMIP antibody clones inhibited metastatic breast cancer cell survival in the brain microenvironment (Example 3). In particular, CEMIP-positive exosomes isolated from brain tropic MDA-MB231 breast cancer cells promoted the survival and proliferation of parental MDA-MB231 cells in the brain microenvironment. However, pre-incubation of CEMIP-positive exosomes with the anti-CEMIP antibody clones resulted in significant growth inhibition, suggesting interferences with CEMIP function.
There is no evidence provided in the specification that the claimed anti-CEMIP clones can be used to treat any and every inflammatory or autoimmune disease in a subject.
While blocking CEMIP signaling may be therapeutically beneficial in some inflammatory/autoimmune disorders, the effectiveness of this approach may be limited depending on specific mechanisms and pathways involved in each disorder. In rheumatoid arthritis (RA) high levels of CEMIP contribute to joint inflammation by degrading hyaluronic acid; and targeting CEMIP with an anti-CEMIP antibody effectively alleviates the severity of arthritis and reduced serum low molecular weight-HA levels and cytokine secretion in collagen-induced arthritis (CIA) mice (Zhang et al, see Abstract and Introduction). However, the etiology of autoimmune diseases involves a complex interplay between genetic and environmental factors. For instance, individuals with particular genetic susceptibilities may have an increased risk of developing autoimmune disorders when encountering specific environmental triggers, including infections, toxins, or stressors (Yasmeen et al, see Abstract and 4th paragraph of Introduction). Many other autoimmune/inflammatory diseases may not involve the CEMIP/HA pathway, thus a CEMIP inhibitory antibody would have no therapeutic benefit as a blanket treatment. For example, there does not appear to be an established link between CEMIP signaling and, for example, type I diabetes or systemic lupus erythematosus. As such, artisans would not reasonably expect the claimed anti-CEMIP antibody to be able to effectively treat these diseases/disorders without evidence to the contrary.
Thus, absent of further evidence, undue experimentation would be required for an artisan to determine the specific patient populations having inflammatory and autoimmune disorders that would receive therapeutic benefit from the claimed methods.
Therefore, the specification is not enabled over the full scope of the claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Rodrigues et al (Rodrigues, Gonçalo et al. “Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis.” Nature cell biology vol. 21,11 (2019): 1403-1412. doi:10.1038/s41556-019-0404-4), hereinafter Rodrigues and Yoshida et al (US20130095110A1), hereinafter Yoshida.
Rodrigues teaches that CEMIP (cell migration-inducing and hyaluronan-binding protein) is elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumor cells impaired brain metastasis, disrupting invasion and tumor cell association with the brain vasculature. Thus, targeting exosomal CEMIP can be a therapeutic intervention for the prevention and treatment of brain metastasis (see Abstract).
Rodrigues does not specifically teach the use of therapeutic antibodies targeting CEMIP to prevent or treat brain metastasis.
However, Yoshida teaches anti-CEMIP (KIAA1199) monoclonal antibodies that can be used a “hyaluronic acid decomposition-inhibiting agent”. Since hyaluronic acid (HA) produced by cancer cells and low molecular weight (LMW)-HA are involved in cancer infiltration and metastasis, then, the anti-CEMIP (KIAA1199) antibody can be used to prevent cancer metastasis (Abstract, Para. 0139-0141, and Para. 0117-0123).
It would have been obvious to one of ordinary skill in the art to make an anti-CEMIP (KIAA1199) inhibitory antibody to prevent or treat brain metastasis in a subject. One of ordinary skill in art would have been motivated to do so since an anti-CEMIP antibody that inhibits hyaluronic decomposition can be used to prevent cancer metastasis as taught by Yoshida, and CEMIP depletion impairs brain metastasis as taught by Rodrigues, Therefore, one of ordinary skill in the art would reasonably expect that an anti-CEMIP antibody that inhibits hyaluronic decomposition can be used in an amount effective to treat or prevent brain metastasis in a subject.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 26 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-15, and 17-21 of copending Application No. 17769245 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims either anticipate or are obvious variants over the instant claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The co-pending claims recite a method of inhibiting metastatic brain disease in a subject comprising selecting a subject having a primary tumor, wherein expression level of CEMIP exosomes derived from primary tumor cells is increased relative to average CEMIP expression levels in exosomes derived from non-tumor cells, and administering to the selected subject a brain metastatic prophylactic agent (co-pending claim 18).
The co-pending claims do not specifically recite that the brain metastatic prophylactic agent is an anti-CEMIP antibody.
However, Rodrigues teaches that CEMIP (cell migration-inducing and hyaluronan-binding protein) is elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumor cells impaired brain metastasis, disrupting invasion and tumor cell association with the brain vasculature. Thus, targeting exosomal CEMIP can be a therapeutic intervention for the prevention and treatment of brain metastasis (see Abstract).
Yoshida further teaches anti-CEMIP (KIAA1199) monoclonal antibodies that can be used a “hyaluronic acid decomposition-inhibiting agent”. Since hyaluronic acid (HA) produced by cancer cells and low molecular weight (LMW)-HA are involved in cancer infiltration and metastasis, then, the anti-CEMIP (KIAA1199) antibody can be used to prevent cancer metastasis (Abstract, Para. 0139-0141, and Para. 0117-0123).
It would have been obvious to one of ordinary skill in the art to use an anti-CEMIP (KIAA1199) that inhibits hyaluronic acid decomposition as the brain metastatic prophylactic agent in order to inhibit metastatic brain disease in a subject in the method of the co-pending claims. One of ordinary skill in art would have been motivated to do so since an anti-CEMIP antibody that inhibits hyaluronic decomposition can be used to prevent cancer metastasis as taught by Yoshida, and CEMIP depletion impairs brain metastasis as taught by Rodrigues, Therefore, one of ordinary skill in the art would reasonably expect that an anti-CEMIP antibody that inhibits hyaluronic decomposition can be used in an amount effective to treat or prevent brain metastasis in a subject.
Conclusion
No claims are allowable. Claims 9 and 10 objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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/LIA E TAYLOR/ Examiner, Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641