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 .
Claims 6, 9, 12, 14-16, 19, 25, 28, 30-37, 39, 42-45, 47, 49, 52, 55, and 59 are pending and are under examination.
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 15, 19, 39, 43, 47, 49, and 52 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.
Claims 19, 39, 43, 47 are indefinite in the recitation of "e.g.”, “for example”, or “such as”. The claims are indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Additionally claim 47 is also indefinite since the use of nested parenthesis in the last three lines makes the claim unclear and indefinite.
Claim 49 contains numerous trademark/trade names, for example, CasodexTM, ErleadaTM, FirmagonTM, etc. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name and, accordingly, the identification/description is indefinite.
Claim 49 is also indefinite in that the claim recites that the therapy “comprises the group consisting of”. Specifically, it is not clear if the claim intendeds to require all the listed therapies, or whether one is selected from the group consisting of. The scope of the claim is unclear and indefinite.
Claims 47 and 49 are also indefinite in the recitation of various second therapies such as, for example, a diet supplement for cancer patients, an androgen inhibitor for treating prostate cancer. The claims depend from claim 34 which is directed to a method of treating a GREM1 related disease or condition, a method of inhibiting FGRF1 activation, or a method of treating a disease or condition associated with FGFR1 activation. It is unclear whether the recitation of supplements “for cancer patients” or androgen inhibitors “for treating prostate cancer”, would require that the treatment method is for treating cancer or prostate cancer, or whether the claim intends only to limit the type of second therapy. For example, would the claims encompass treating a fibrotic condition in combination with an androgen inhibitor that is used for treating prostate cancer, or would the claims require treating prostate cancer when an androgen inhibitor for treating prostate cancer is administered.
Claim 15 recites NanobodyTM, which is a trademark and is indefinite for the same reasons set forth above.
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 6, 12, 14-16, 19, 25, 28, 30-37, 39, 42-45, 47, 49, 52, 55, and 59 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. Specifically, there is insufficient written description to demonstrate that applicant was in possession of the claimed genus of antibodies against human gremlin1 or antigen binding fragments thereof.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, 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 claimed genus. See MPEP 2163.
The instant claims are directed to a genus of antibodies or antibody fragments against human gremlin1, wherein the antibodies or antigen binding fragments there comprise a VH and/or a VL region having certain CDRs as defined in a)-k). Thus, the claims encompass a genus of antibodies or antibody fragments defined by a partial structure, either three VH CDRs or three VL CDRs. For example, the claims would encompass an antibody against human gremlin1 having a VH with CDRs of SEQ ID Nos: 1-3, and any VL.
The state of the art is such that the 6 CDRs of an antibody are critically involved in antigen binding, that even single amino acid changes can alter antigen specificity of binding, and that CDR mutations are unpredictable in terms of affinity, specificity, and solubility, and are also context dependent (see Hall, 1992, and Rabia, 2018). Furthermore, antibody variable regions are composed of a heavy and light chain variable regions, each involved in providing for binding specificity. Variability in the antigen binding site is achieved by V(D)J recombination via heavy and light chain pairing, with the most diverse regions being the 6 CDR regions in the heavy and light chain. While the heavy variable region is the most diverse, light chain variable regions are also important for binding specificity of antibodies, and swapping light chains can change the antigen specificity of the antibody (see Townsend et al., 2016, pages 1-2, in particular). Furthermore, the light chain repertoire is extremely diverse being encoded by kappa and lambda gene segments, each with different V and J genes. For example, Townsend teaches analysis of 29,000 distinct light chains having significant differences in physiochemical properties. See also Janeway, which teaches that the antibody repertoire in humans is at least 1011, with a large degree of diversity in both heavy and light chains. For kappa light chains, there are approximately 40 functional V gene segments and five J gene segments, and thus potentially 200 different Vkappa regions. Janeway teaches that for lambda light chains, there are approximately 30 functional V lambda segments and four J gene segments yielding 12 possible V lambda regions, so in all 320 different light chains can be make as a result of combination different light chain gene segments. These can also be further varied by a process of somatic hyper mutation. Furthermore, the diversity of the immunoglobulin repertoire is mediated in part by different combination so heavy and light chain V regions that pair to form a unique antibody binding site. See, for example, Rabia, 2018, which teaches that the maximal chemical diversity of antibody CDRs is unimaginably large and is extremely challenging to define the sequence determinant of antibody specificity (see page 4).
The instant specification in Table 1 discloses certain VH/VL pairings having CDRs as defined in a)-k) of the instant claims. However, this is not sufficiently representative of the broad genus of antibodies or antibody fragments defined by only VH or VL CDRs as encompassed in the instant claims.
The instant application has not provided a sufficient description showing possession of the necessary 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 of antibodies and inhibitors encompassing various structures, specificities and functions. Further, the Court has interpreted 35 U.S.C. §112, first paragraph, to require the patent specification to “describe the claimed invention so that one skilled in the art can recognize what is claimed. Enzo Biochem, Inc. v. Gen-Probe Inc, 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002).
In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s “disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 43 USPQ2d 1398 (Fed Cir. 1997)).
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.)
Also, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., lnc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Meeting the written description threshold requires showing that the applicant was in “possession” of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning – i.e., what the written description and knowledge in the art would lead one to speculate as to modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also ensures that when a patent claims a genus by function, the specification recites sufficient materials to accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3. Note the following Court Decisions regarding the written description of antibodies in the context of the current claims.
Given the claimed broadly class of antibodies, in the absence of sufficient disclosure of relevant identifying characteristics, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014) and the specification at best describes plan for making antibodies with the “limitations above” and then identifying those that satisfy claim limitations, but mere “wish or plan” for obtaining claimed invention is not sufficient. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011). There is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed antibodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
Claims 6, 12, 14-16, 19, 25, 28, 30-37, 39, 42-45, 47, 49, 52, 55, and 59 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:
An isolated antibody against human gremlin1 or an antigen binding fragment therefore comprising a VH region and a VL region, wherein the VH HCDR1-3 and the VL LCDR1-3 comprise the CDRs as defined in a)-k) of claim 6; and a method of treating cancer in a subject, or a method of inhibiting FGFR1 activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of said antibody or antigen binding fragment thereof;
does not reasonably provide enablement for:
An isolated antibody against human gremlin1 or an antigen binding fragment therefore, comprising a VH region or a VL region, wherein the VH HCDR1-3 and the VL LCDR1-3 comprise the CDRs as defined in a)-k) of claim 6; or a method of treating a GREM1-related disease or condition, a method of treating a disease or condition associated with FGFR1 activation mediated by GREM1, a method of treating a disease that can benefit from increasing BMP7 activity or reducing gremlin-mediated inhibition of BMP7 activity or increasing efficacy of BMP7 treatment in a subject, comprising administering to the subject a therapeutically effective amount of said antibody or antigen binding fragment thereof.
The specification disclosure is insufficient to enable one skilled in the art to practice the invention as claimed without an undue amount of experimentation. Undue experimentation must be considered in light of factors including: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill in the art, the level of predictability of the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention, in re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
“The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.” In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling (MPEP 2164.03)” The MPEP further states that physiological activity can be considered inherently unpredictable.
The instant claims are directed to a genus of antibodies or antibody fragments against human gremlin1 (or polynucleotides encoding said antibodies or methods of using said antibodies), wherein the antibodies or antigen binding fragments thereof comprise a VH and/or a VL region having certain CDRs as defined in a)-k). Thus, the claims encompass a genus of antibodies or antibody fragments defined by a partial structure, either three VH CDRs or three VL CDRs. For example, the claims would encompass an antibody against human gremlin1 having a VH with CDRs of SEQ ID Nos: 1-3, and any VL.
The state of the art is such that the 6 CDRs of an antibody are critically involved in antigen binding, that even single amino acid changes can alter antigen specificity of binding, and that CDR mutations are unpredictable in terms of affinity, specificity, and solubility, and are also context dependent (see Hall, 1992, and Rabia, 2018). Furthermore, antibody variable regions are composed of a heavy and light chain variable regions, each involved in providing for binding specificity. Variability in the antigen binding site is achieved by V(D)J recombination via heavy and light chain pairing, with the most diverse regions being the 6 CDR regions in the heavy and light chain. While the heavy variable region is the most diverse, light chain variable regions are also important for binding specificity of antibodies, and swapping light chains can change the antigen specificity of the antibody (see Townsend et al., 2016, pages 1-2, in particular). Furthermore, the light chain repertoire is extremely diverse being encoded by kappa and lambda gene segments, each with different V and J genes. For example, Townsend teaches analysis of 29,000 distinct light chains having significant differences in physiochemical properties. See also Janeway, which teaches that the antibody repertoire in humans is at least 1011, with a large degree of diversity in both heavy and light chains. For kappa light chains, there are approximately 40 functional V gene segments and five J gene segments, and thus potentially 200 different Vkappa regions. Janeway teaches that for lambda light chains, there are approximately 30 functional V lambda segments and four J gene segments yielding 12 possible V lambda regions, so in all 320 different light chains can be make as a result of combination different light chain gene segments. These can also be further varied by a process of somatic hyper mutation. Furthermore, the diversity of the immunoglobulin repertoire is mediated in part by different combination so heavy and light chain V regions that pair to form a unique antibody binding site. See, for example, Rabia, 2018, which teaches that the maximal chemical diversity of antibody CDRs is unimaginably large and is extremely challenging to define the sequence determinant of antibody specificity (see page 4). Thus, making and using a genus of antibodies or antibody fragments having only 3 defined VH CDRs or 3 defined VL CDRs would be highly unpredictable.
Furthermore, the claims would encompass antigen binding fragments having only a VH or VL. Furthermore, claim 15 recites antibody fragments such as a domain antibody, bivalent domain antibody, an Fd fragment a camelized single domain antigen, a NANOBODYTM, which comprise only a VH or a VL. The state of the art is such conventional antibodies are exclusively expressed as paired heavy and light chains, and simply removing the VL domain in antibodies that were selected for binding in the presence of a cognate VL does not result in a functional, stable, domain antibody (see Rouet, 2015 and Holt et al., page 485, in particular). Thus, making and using the genus of antibody fragments comprising only a VH or a VL as encompassed by the present claims would be highly unpredictable.
Furthermore, the claims encompass methods of treating any GREM1-related disease or condition, any disease or condition associated with FGFR1 activation mediated by GREM1, any disease that can benefit from increasing BMP7 activity or reducing gremlin-mediated inhibition of BMP7 activity, or methods of increasing efficacy of any BMP7 treatment in a subject, comprising administering to the subject said antibodies or fragments thereof. The state of the art is such that treating diseases with gremlin-1 antibodies is highly unpredictable. For example, gremlin-1 antibodies are not effective in treating liver fibrosis and do not reduce liver inflammation or liver fibrosis, even when the antibodies block binding of gremlin to BMPs (see Horn, 2024). Thus, treating the diseases encompassed by the instant claims, would be highly unpredictable.
Thus, based on the breadth of the claims and the unpredictability of the art, the instant specification must provide a sufficient and enabling disclosure, commensurate in scope with the instant claims. The instant specification discloses gremlin1 antibodies having defined VH/VL pairs that were produced by immunizing mice with a human gremlin1 protein. No other guidance or examples are provided for any VH or VL that can be paired with the three VH or VL CDRs in claim 6, while functioning to bind to human gremlin1. Furthermore, no examples or guidance are provided for antibody fragments, such as domain antibody, bivalent domain antibody, an Fd fragment a camelized single domain antigen, a NANOBODYTM, that comprise only a VH or a VL of said antibodies that function to bind to Gremlin1. The instant specification discloses that the antibodies can decrease tumor volume and decrease tumor growth in a treated subject, however, no guidance or examples are provided regarding treating other Gremlin1, FGRF1, or BMB7 associated diseases, as encompassed by the present claims. Thus, based on the breadth of the claims, the unpredictability of the art, and the lack of guidance provided by the instant specification, it would require undue experimentation to make and use the antibodies and antibody fragments as broadly claimed.
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 6, 9, 12, 14-16, 19, 25, 28, 30-37, 39, 42-45, 47, 49, 52, 55, and 59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 7-10, 12-13, 15, 17, 19-20, 23, 25, 28, 31, 37, 40, 43, 47-49, 56, 58, 61 of copending Application No. 18/549,928 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘928 application claims a method of treating a GREM-1 expressing cancer or fibrotic disease comprising administering to a subject a GREM1 antagonist, and claims that the antagonist is an antibody comprising the same CDRs as recited in a)-d), or the same VH and VL of the instant claims (i.e. the claims of the ‘928 application cover the same antibodies of the instant claims). The ‘928 application claims that the antibody is humanized or IgG1, or bispecific, wherein the bispecific antibody also targets PD-`, or administering a second therapeutic agent such as an androgen axis inhibitor degarelix. The ‘928 application claims that the cancer is triple negative breast cancer, or esophageal cancer. Although not specifically claimed in the ‘928 application, it would be obvious to produce the antibody recombinantly by expressing it in a host cell from a polynucleotide as is well known in the art. Furthermore, it would be obvious to further test the treated subjects for GREM1 antagonist activity (i.e. to test whether a sample from the subject has reduced GREM1 using the antagonist antibody) in order to monitor the efficacy of the treatment method.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
No claim is allowed.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644