DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s amendment filed on December 9, 2025 is acknowledged.
Claims 1-20 are pending.
Claims 4, 5, and 7 stand withdrawn under 37 CFR 1.142(b) as being drawn to nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 12, 2025.
Claims 1-3, 6, and 8-20 are currently under consideration as they read on the elected species of L234A substitution.
3. Applicant’s amendment to the specification is acknowledge.
4. In view of applicant’s amendment, following rejections are set forth.
5. 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.
6. Claims 1-3, 6, and 8-20 stand 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 for the reasons of record.
The claims are drawn to a method of treating inflammatory bowel disease in a subject in need thereof by administering an effective amount of a pharmaceutical composition comprising an engineered protein construct comprising a Triggering Receptor Expressed on Myeloid Cells (TREM1) binding VH, an IL-23 binding VH and a heterodimeric Fc region, wherein the composition is sufficient to treat inflammatory bowel disease. Dependent claims, e.g. claims 8-10, further recites functions of the TREM1 binding VH such as inhibits binding of one or more TREM1 ligands to TREM1. Dependent claims, e.g. claims 11-20, recite that the engineered construct has increased anti-inflammatory activity compared to a monospecific antibody that binds TREM1 and monospecific antibody that binds to IL-23.
The specification discloses exemplified VH and VL sequences for binding to protein from IL-23 family (e.g. see Table 28 in page 63 of the specification as-filed). The specification discloses that TREM1, also known as CD354, is highly expressed on subsects of myeloid cells including neutrophil, monocytes, and macrophages and is implicated in inmate and adaptive immune function by amplifying inflammatory response (e.g. see [0167] in page 63 of the specification as-filed). Further, the specification discloses heavy chain VH CDRs 1-3 amino acid sequences in Table 30 and VH amino acid sequences for TREM1 in Table 31. In Tables 32 and 34 of the instant specification, applicant discloses light chain CDRs sequences and VL sequences, respectively. Furthermore, the specification discloses one example of bispecific antibodies that binds TREM1 and IL-23 comprises VH/VL that binds TREM1 and a VH for IL-23 binding but no evidence was shown that VH alone without the matching VL would bind IL-23 (e.g. see Example 4 in pages 138-139 of the specification as-filed).
There is insufficient written description in the specification as-filed of the engineered protein construct comprising a TREM1 binding VH and an IL-23 binding VH for the method of treating inflammation bowel disease or a method of treating at least one symptom associated with an inflammatory condition as recited in the instant claims.
Applicant’s arguments have been fully considered but have not been found persuasive.
Applicant argues that the claims have been amended to recite TREM1 binding VH and VL and an IL-23 binding VH and VL and effective amount being sufficient to treat TREM1 associated inflammation. Further, applicant asserts that a skilled person with knowledge of the art and familiar with the instant application would be able to envision the claimed engineered constructs and methos for using them in a pharmaceutical composition for treating inflammatory disease or condition by advantageously reducing the inflammatory via direct inhibition of proinflammatory cytokines and indirect inhibition of proinflammatory cytokine production by binding to TREM1. Applicant further asserts that the specification fully supports the genus of the engineered protein construct recited in the amended claims simply by reciting VH/VL for each of the binding domains.
As such, applicant asserts that the instant specification provides sufficient written description support for the instant claims.
This is not found persuasive for following reasons:
Contrary to applicant’s assertion relying upon claim amendments, note that the amended claims still do not recite any structural features of the VH and VL, e.g. amino acid sequences of each VH and VL. Further, while the claims recite the use of a genus of engineered protein construct comprising TREM1 binding VH and VL domains and IL-23 binding VH and VL domains, the instant specification does not provide sufficient description of a genus of either a representative number of species falling within the scope of the gnus or structural features common to the member of the genus so that one of skill in the art can visualize or recognize the members of the genus of the engineered protein construct. For example, the species VH of anti-24 antibodies disclosed in Table 23 in page 55 of the specification and the VL in Table 27 in page 61 of the specification as-filed do not appear to share a common structure fall within the scope of the genus so that one of skill in the art would recognize the members of the genus. There is insufficient disclosure of relevant identifying characteristics sufficient to describe the claimed engineered protein construct that would correlate with the function of TREM1 binding and IL-23 binding sufficient to treat TREM1 associated inflammation thereby by treating inflammatory bowel disease in a subject.
Further, a generic recitation of engineered protein construct comprising a TREM1 binding VH and VL and an IL-23 binding VH and VL without more is not an adequate written description if the genus because it does not define any structural features commonly possessed by the members of the genus.
Therefore, in view of the breadth of the claims and the generic nature of the instant specification, artisans would reasonably conclude that applicant was not in possession of the full breadth of the engineered protein construct comprising TREM1 binding VH and VL and an IL-23 binding VH and VL at the time the instant application was filed. Logically, if applicant was not in possession of the engineered protein construct which is being administered, applicant also was not in possession of methods of administering such reagents at the time the instant application was filed.
7. Claims 1-3, 6, and 8-20 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 for the reasons of record.
The claims are drawn to a method of treating inflammatory bowel disease in a subject in need thereof by administering an effective amount of a pharmaceutical composition comprising an engineered protein construct comprising a Triggering Receptor Expressed on Myeloid Cells (TREM1) binding VH, an IL-23 binding VH and a heterodimeric Fc region, wherein the composition is sufficient to treat inflammatory bowel disease. Dependent claims, e.g. claims 8-10, further recites functions of the TREM1 binding VH such as inhibits binding of one or more TREM1 ligands to TREM1. Dependent claims, e.g. claims 11-20, recite that the engineered construct has increased anti-inflammatory activity compared to a monospecific antibody that binds TREM1 and monospecific antibody that binds to IL-23.
The specification discloses exemplified VH and VL sequences for binding to protein from IL-23 family (e.g. see Table 28 in page 63 of the specification as-filed). The specification discloses that TREM1, also known as CD354, is highly expressed on subsects of myeloid cells including neutrophil, monocytes, and macrophages and is implicated in inmate and adaptive immune function by amplifying inflammatory response (e.g. see [0167] in page 63 of the specification as-filed). Further, the specification discloses heavy chain VH CDRs 1-3 amino acid sequences in Table 30 and VH amino acid sequences for TREM1 in Table 31. In Tables 32 and 34 of the instant specification, applicant discloses light chain CDRs sequences and VL sequences, respectively. Furthermore, the specification discloses one example of bispecific antibodies that binds TREM1 and IL-23 comprises VH/VL that binds TREM1 and a VH for IL-23 binding but no evidence was shown that VH alone without the matching VL would bind IL-23 (e.g. see Example 4 in pages 138-139 of the specification as-filed).
However, 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.
Applicant’s arguments have been fully considered but have not been found persuasive.
Applicant asserts that specification provides some VH and VL amino acid sequences forming IL 23 binding domains and TREM1 binding domains, e.g. in Tables 28, 30, and 31, and Example 4 in the instant specification discloses how to make the construct and measure its activities. Applicant asserts that the generation of antibodies to a known antigen is routine as evidenced by the references cited by the Examiner. As such, applicant asserts that the claimed method is enabled.
This is not found persuasive for following reasons:
Contrary to applicant’s reliance on the disclosed antibody species, note that the enablement requirement refers to the requirement of 35 U.S.C. 112, 1st paragraph that the specification must describe the invention in such terms that one skilled in the art can make and use the claimed invention.
In Amgen Inc. et al. v. Sanofi et al., 143 S. Ct. 1243 (2023), the Supreme Court held that ‘‘[i]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class. . . . The more one claims, the more one must enable.’’ The Supreme Court clarified that the specification does not always need to ‘‘describe with particularity how to make and use every single embodiment within a claimed class.’’ Id. at 1254. Rather, the specification may require a reasonable amount of experimentation to make and use the invention, and what is reasonable will depend on the nature of the invention and the underlying art. For example, ‘‘it may suffice to give an example (or a few examples) if the specification also discloses some general quality . . . running through the class that gives it a peculiar fitness for the particular purpose,’’ and ‘‘disclosing that general quality may reliably enable a person skilled in the art to make and use all of what is claimed, not merely a subset.’’ Id. at 1254–1255 (internal quotations omitted). The Supreme Court, citing Wood v. Underhill, 46 U.S. 1 (1846), and Minerals Separation, Ltd. v. Hyde, 242 U.S. 261 (1916) (hereafter Minerals Separation), stated that the specification may call for a reasonable amount of experimentation to make and use the claimed invention. Amgen, 143 S. Ct. at 1246. The Court in Amgen, citing to Minerals Separation, opined that ‘‘[w]hat is reasonable in any case will depend on the nature of the invention and the underlying art.’’ Id. That reasonableness standard is still the one to be applied following the Supreme Court decision in Amgen.
Here, there is insufficient objective evidence that the specific anti-TREM1 antibodies and the anti-IL-23 antibodies having specific amino acid sequences for the VH and VL as disclosed in the specification as filed, can be extrapolated to provide enabling description of currently recited methods commensurate in scope with the claimed invention.
Further, contrary to applicant’s assertion, there is no working examples of the claimed method of treating inflammatory bowel disease by administering the engineered protein construct comprising a TREM1 binding VL and VL and an IL-23 binding VH and VL, where in the effective amount of the construct is sufficient to treat TREM1 associated inflammation, thereby treating inflammatory bowel disease.
Once again, the method of treating inflammatory bowel disease by targeting TREM1 can be unpredictable. For example, Pincetic et al. (US 2025/0092131) teach that TREM1 antibodies can be agonist and antagonist but no agonist antibodies that activate TREM1 in solution or synergizing with TREM1 ligands have been described, nor have been the antagonist antibodies that block TREM1 function by binding to multiple sites (e.g. see left col. in page 3).
Therefore, the instant specification fails to provide sufficient guidance and direction to identity and to enable any or all engineered protein construct comprising a TREM1 binding domain VH/VL and an IL-23 binding VH/VL without structural elements of the binding domains. Consequently, the experimentation left to those skilled in the art to make and use the recited construct in a method of treating inflammatory bowel disease or a method of treating at least one symptom associated with an inflammatory condition including headache, nausea, vomiting, rectal bleeding, diarrhea, and back pain is unnecessarily, improperly, and extensive and undue.
As such, applicant’s arguments have not been found persuavie.
8. 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.
9. 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.
9. Claims 1-3, 6, and 8-20 are rejected under 35 U.S.C. 103 as being unpatentable over Pincetic et al. (US 2020/0131264) in view of Almradi et al. (BioDrus 2020, 34:713-721) and Yang et al. (US 2021/0061925) as evidenced by the disclosure in pages 108-109 of the instant specification as filed for the reasons of record.
Pincetic et al. teach anti-TREM1 antibodies comprises a VH and a VL, and a pharmaceutical composition comprises the antibodies (e.g. see Abstract, [0016], claims 111-133, and [0036]). Pincetic et al. further teach that that anti-TREM1 antibodies are human IgG1 and can have amino acid substitutions including L234A, L235A, and P329A (e.g. see [0025]). Pincetic et al. teach that TREM1 is involved in human inflammatory bowel disease and anti-TREM1 antibody can be used to treat multiple inflammatory disorders where excessive myeloid cell activation or survival is pathogenic such as inflammatory bowel disease (IBD) (e.g. see [0007], [0013], [0306], Example 50). Pincetic et al. teach the anti-TREM1 antibodies can be in a bispecific form recognizing a first antigen and a second antigen such as (e.g. see [0195], [0231]). Pincetic et al. teach heterodimeric antibody having different substitutions in first CH3 region and the second CH3 region (e.g. see [0349]). Pincetic et al. teach that the classic sign of acute inflammation are pain and loss of function and anti-TREM1 antibodies are useful for treating inflammation [e.g. see [0246]-[0250]). Therefore, it is reasonable that anti-TREM1 antibodies would be able to treat pain via their anti-inflammatory effect.
The reference teachings differ from the instant invention by not describing an IL-23 binding VH and VL.
Almradi et al. teach IL-23 is an essential cytokine in the pathogenesis of IBD and a highly promising treatment target because of its role in differentiation and maturation of Th17 cells that mediates the development and maintenance of inflammation (e.g. see Title and Key Points in page 713). Almradi et al. teach that administration of Lactobacillus acidophilus suppressed IL-23 and Th17 cytokine production in experimental DSS colitis, treatment of mice with TNBS (e.g. see right col. in page 2).
Almradi et al. teach anti-IL-23 antibody Risankizumab is more effective than placebo for inducing clinical remission in patients with active Crohn’s Disease (e.g. see 1st full paragraph in right col. in page 6).
Yang et al. teach a bispecific antibody comprising a VH chain A and VL chain A forming a first antigen binding domain and a VH chain B and a VL chain B forming a second antigen binding domain, and a heterodimeric Fc region comprising two constant regions, e.g. see FIG. 1A or copy below:
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Yang et al. teach that the two Fc region is heterodimeric with one Fc comprises amino acid substitutions L234A, L235A, and P329A and the Fc is from human IgG1 (e.g. see [0530]). Yang et al. teach that bispecific antibody that binds to various antigens including TREM1 and IL23 (e.g. see claim 120). Yang et al. teach that the binding protein is useful for neutralizing cytokine activities and treating inflammatory disorders (e.g. see [0546]).
As evidenced by the instant specification, the claimed SEQ ID NO:453 is the amino acid sequence of the naturally occurring human IgG Fc region (e.g. see pages 108-109 of the specification as-filed). Therefore, Yang’s human IgG1 from which the L234A, L235A, and P329A were made from would inherently have the same amino acid sequences of SEQ ID NO:453 as recited in the instant claims.
It would thus be obvious to one of ordinary skill in the art at the time the invention was filed to combine the teachings of the prior art to make a bispecific antibody comprising two antigen binding domains, each comprises a VH and a VL that binds TREM1 and IL-23 as well as two heterodimeric Fc regions and administered the bispecific antibody to treat inflammatory bowel disease.
On of ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success, because Pincetic et al. teach anti-TREM1 antibody and its bispecific form having Fc mutations is useful for treating IBD, Almradi et al. teach anti-IL-23 antibody is effective in treating IBD. An ordinary skill in the art would have been motivated to combine the two known anti-TREM1 antibody and the anti-IL-23 antibody following the methods of producing bispecific antibody having two heterodimeric Fc region to produce a bispecific anti-TREM1 and anti-IL-23 antibody with the Fc mutations that facilitate the formation of heterodimers.
Given the well-known therapeutic effects of the antibodies targeting TREM1 and IL-23 in treating IBD, an ordinary skill in the art would be able to administer such antibody in a method of treating IBD with a reasonable expectation of success. Given that the combined teachings of the prior art yielded the same method of treating IBD by administering the same bispecific antibody, the prior art methods would have inherently achieved the same results as the instantly claimed methods, e.g. inhibits binding of one or more TREM1 ligand to TREM1 or treating at least one symptom associated with inflammatory condition (e.g. IBD) as recited in instant claims 8-20.
Applicant’s arguments have been fully considered but have not been found persuasive.
Applicant acknowledges that Pincetic et al. anti-TREM1 antibody in treating human inflammatory bowel disease but asserts that Pincetic et al. do not teach anti-IL-23 antibody. Applicant further argues that Almradi suggested anti-IL-23 antibody in treating inflammatory bowel disease but does not teach a bispecific anti-TREM1 antibody and anti-IL-23 antibody.
Furthermore, applicant argues that Yang disclosed large number of antibodies and large number of antigens that can be targeted. Applicant argues that the Examiner has not identified guidance in Yang for selecting TREM 1 and IL-23 among the large number of antigens recited in claim 120 for a successful result. Thus, applicant argues that Yang combined with other references cited by the Examiner would not provide reasonable expectation of success for treating inflammatory conditions including inflammatory bowel disease.
This is not found persuasive for following reasons:
Contrary to applicant’s arguments, note that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually “[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA].” In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012). Also see MPEP 2145 IV.
Here, once again, given that it was well-known that both anti-TREM1 antibody and anti-IL23 antibody are therapeutic to inflammatory bowel disease as taught by Pincetic et al. and Almradi, and in view of the well-known technology of making bispecific antibody disclosed by Yang et al., an ordinary skill in the art would have been motivated to combine the two known anti-TREM1 antibody and the anti-IL-23 antibody following the methods of producing bispecific antibody having two heterodimeric Fc region to produce a bispecific anti-TREM1 and anti-IL-23 antibody with the Fc mutations that facilitate the formation of heterodimers with a reasonable expectation of success.
As such, applicant’s arguments have not been found persuaive.
10. No claim is allowed.
11. THIS ACTION IS MADE FINAL. 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.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHUN W DAHLE/Primary Examiner, Art Unit 1641