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. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 7, 2026 has been entered.
Claim 2 has been canceled.
Claim 21 has been added.
Claims 1 and 3-21 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Claims 4, 5, and 7 stand withdrawn under 37 CFR 1.142(b) as being drawn to nonelected species, there being no allowable generic or linking claim.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. In view of applicant’s amendment, following rejections are set forth.
4. 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.
5. Claims 1, 3, 6, and 8-21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A) Claims 1, 3, 6, and 8-21 are indefinite in the recitation of “wherein contacting cells in vitro with the bispecific anti-inflammatory IgG antibody results in a lower secretion of at least one inflammatory biomarker selected from a group consisting of IL-17A, IL-lb and TNFa by the cells as compared to contacting comparable cells with a comparable amount of a corresponding monospecific TREM1 binding antibody, a corresponding monospecific IL-23 binding antibody, or a combination thereof” because the metes and bounds of the phrase is ambiguous. It is not clear if the wherein clause is reciting an active method step of the instant method of treating inflammatory bowel disease. For the purpose of examination and application of prior art, this wherein clause is read and describing the feature of the bispecific antibody rather than an active method steps.
B) The term “a lower secretion” in claim 21 is a relative term which renders the claim indefinite. The term “a lower secretion” of at least one biomarker is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
6. 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.
7. Claims 1, 3, 6, and 8-21 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 for the reasons of record.
The claims are drawn to a method of treating inflammatory bowel disease or treating at least one symptom associated with an inflammatory condition in a subject in need thereof by administering an effective amount of a pharmaceutical composition comprising a bispecific anti-inflammatory IgG antibody that comprises a Triggering Receptor Expressed on Myeloid Cells (TREM1) binding VH and VL, an IL-23 binding VH and VL, and a heterodimeric Fc region, wherein the heterodimeric Fc region is operably linked to the TREM1 binding VH and the IL-23 binding VH, wherein the composition is sufficient to treat TREM1 associated inflammation, thereby treating inflammatory bowel disease, and wherein contacting cells in vitro with the bispecific anti-inflammatory IgG antibody results in a lower secretion of at least one inflammatory biomarker selected from a group consisting of IL-17A, IL-lb and TNFa by the cells as compared to contacting comparable cells with a comparable amount of a corresponding monospecific TREM1 binding antibody, a corresponding monospecific IL-23 binding antibody, or a combination thereof.
Dependent claims, e.g. claims 8-10, further recites functions of the TREM1 binding VH such as inhibiting 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 bind 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 bispecific anti-inflammatory IgG antibody 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.
The amended claims added more functional limitations, e.g. a bispecific anti-inflammatory IgG antibody, the Fc region is operably linked to the VH domains, and in vitro features of the bispecific antibody compared to the monospecific antibodies. However, what is missing is the structure of the antibody (specifically the amino acid sequences of the VH and VL or the six CDRs) that would correlate to these functions.
As previously stated in the Office Action mailed on September 10, 2025, artisans are well aware that knowledge of a given antigen (for instance human CD40) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document). Similarly, Lloyd et al. (Protein Engineering Design & Selection 2009, 22;3:159-168) teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding, as their sequencing studies revealed that out of 841 unselected and 5,044 selected antibodies, all but one of the 49 functional VH gene segments was observed (see entire document). Goel et al. (The Journal of Immunology, 2004, 173:7358-7367) disclose the synthesis of three mAbs that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (see entire document).
As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequence bound in a population of antibodies that bind to a given antigen no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen.
Indeed, Kanyavuz et al. (Nature Review Immunology, 2019, 19: 355-368) teach that “Theoretically, under physiological conditions, the human immune system can generate BCRs with 1026 distinct sequences, an astronomical number that is far greater than the calculated number of all B cell clones that can be generated during the lifespan of a healthy human (estimated to be 4 × 1014).
Regarding the claimed method of treating inflammatory bowel disease or symptoms associated with inflammation by administering protein construct that binds TREM1 and IL-23, note that 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).
It is noted that applicant has not claimed a product, but rather a method of administering a product. However, artisans must reasonably be in possession of a product in order to be in possession of methods of administering said product. As has already been pointed out none of the instant claims recite any structure for the administered product that provides for the functions such as sufficiently treating inflammatory bowel disease or directly inhibits TREM1 activity or a target sweeping activity by binding to TREM1 as recited in claims, e.g. claims 1, 10, 16, 18-21). Thus, all present claims utilize only functional language to describe the product- the engineered protein construct which is necessarily administered in the instant claims.
The specification does disclose several specific antibodies comprising VH and VL amino acid sequences for binding TREM1 and IL-23. The specification also discloses IL-23 family includes IL-23α, a fragment thereof, a variant thereof, a multimeric form thereof or combination thereof, as well as IL-23 family protein that binds IL-23 receptor (e.g. see [0152] of the specification as-filed). The specification discloses the amino acid sequences of human TREM1 (e.g. see [0169]).
The disclosure of the antigens IL-23 and TREM1 and the species of antibodies with specific sequences do not serve to provide a written description of the bispecific anti-inflammatory IgG antibody comprising TREM1 binding VH/VL and IL-23 binding VH/VL as it does not identify any specific structural feature of the VHs and the VLs that would form the binding to the antigens or provide any combination of features which give rise to the functions described above.
It is noted that the specification does disclose species of the specific anti-IL-23 antibodies and anti-TREM1 antibodies comprising specific amino acid sequences for the VH and the VL chains forming functional binding domains for the antigens.
However, these species of antibodies are not reasonably representative of the species of all possible TREM1 binding VH/VL domains and an IL-23 binding VH/VL domains because of the structural diversity found in antibodies that bind the same antigen as discussed by for example Edwards et al., Llyod et al., and Goel et al. discussed above. Further, as has been discussed above, identifying an antibody simply on the basis of what it binds and what it does rather than by identifying the sequence/structure of the antibody in question is generally insufficient to provide sufficient written description of the antibody in question.
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/VL and an IL-23 binding VH/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.
Applicant’s arguments in conjunction with the Vemuri declaration under 37 CFR 1.132 have been fully considered but have not been found persuasive.
Applicant asserts that the claims have been amended to recite a bispecific anti-inflammatory IgG antibody and with the in vitro feature of resulting in a lower secretion of at least one inflammatory biomarker including IL-17A as compared to monospecific antibody. Applicant asserts that the Office must provide evidence or reasoning to rebut the notion that a bispecific anti-inflammatory IgG antibody that binds TREM1 and IL-23 cannot cause the reduction in TREM1-associated inflammation in a subject suffering from inflammatory bowel disease.
Applicant argues that the specification discloses how to make antibodies within the scope of the amended claims and how to test the results in Examples 3 and 4 as well as [0210] of the specification as-filed.
The Vemuri declaration states that contacting PBMC cells with the bispecific antibody resulted in greater reduction in secretion of inflammatory markers, IL-17A, IL-1b and TNFα compared with the monospecific antibody groups. As such, applicant asserts that a person skilled in the art would understand that applicant is in possession of the method of treatment recited in amended claims 1 and 20.
As such, applicant asserts that the rejection should be withdrawn.
This is not found persuasive for following reasons:
In contrast to applicant’s reliance on the claim amendment, note that the amendments do not add the structure of the antibodies, namely the actual amino acid sequences for the VH and VL that would correlate with the functions. Merely adding the limitations of “a bispecific anti-inflammatory IgG antibody” and the in vitro features of IgG antibody is insufficient to demonstrate that the claims satisfy the written description requirement because the bispecific antibodies disclosed in the instant specification encompass distinct and diverse structures and do not encompass common structural elements essential to the function of being an anti-inflammatory IgG antibody with the in vitro features of capable of lower secretion of at least one inflammatory biomarker and to be able to treat inflammatory bowel disease.
Contrary to applicant’s arguments that the Examiner must demonstrate evidence that a bispecific anti-inflammatory IgG antibody that binds TREM1 and IL-23 cannot cause the reduction in TREM1-associated inflammation in a subject suffering from inflammatory bowel disease, note that this is not the burden on the Examiner about the written description requirement.
Rather, the written description requirement for a claimed genus of the bispecific antibody may be satisfied through sufficient description of a representative number of species.
Further, it was known in the art that anti-TREM1 antibody can be agonist or antagonist as disclosed by that Pincetic et al. (US 2025/0092131) as discussed above. There is insufficient objective evidence in the instant specification, applicant’s REMARK or the Vemuri declaration to show that these two types of anti-TREM1 antibodies having opposite effects would be expected to have the same functions recited in the instant claims. The Vemuri declaration using specific bispecific antibody is not commensurate in scope of the instant claims which are drawn to the use of any or all bispecific antibody that binds TREM1 and IL-23.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
While the instant specification discloses more than one species of antibodies, these species do not share common structures essential to the functions as recited in the instant claims. Further, applicant is relying upon the antigens TREM1 and IL-23 and certain biological activities (e.g. anti-inflammatory and in vitro features) to support the entire genus of the bispecific anti-inflammatory IgG antibody. However, guidance of how to make the bispecific antibody with certain features is not sufficient to demonstrate possession of the genus.
The antibody species disclosed in the instant specification is not reasonably representative of the species of all possible antibody because of the structural diversity found in antibodies that bind the same antigen as discussed by for example Edwards et al., Llyod et al., and Goel et al. discussed above.
Further, as has been discussed above, identifying an antibody simply on the basis of what it binds rather than by identifying the sequence/structure of the antibody in question is generally insufficient to provide sufficient written description of the antibody in question.
As such, applicant’s arguments have not been found persuasive.
8. Claims 1, 3, 6, and 8-21 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 or treating at least one symptom associated with an inflammatory condition in a subject in need thereof by administering an effective amount of a pharmaceutical composition comprising a bispecific anti-inflammatory IgG antibody that comprises a Triggering Receptor Expressed on Myeloid Cells (TREM1) binding VH and VL, an IL-23 binding VH and VL, and a heterodimeric Fc region, wherein the heterodimeric Fc region is operably linked to the TREM1 binding VH and the IL-23 binding VH, wherein the composition is sufficient to treat TREM1 associated inflammation, thereby treating inflammatory bowel disease, and wherein contacting cells in vitro with the bispecific anti-inflammatory IgG antibody results in a lower secretion of at least one inflammatory biomarker selected from a group consisting of IL-17A, IL-lb and TNFa by the cells as compared to contacting comparable cells with a comparable amount of a corresponding monospecific TREM1 binding antibody, a corresponding monospecific IL-23 binding antibody, or a combination thereof.
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.
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, 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 (Janeway Jr et al., Immunology, 3rd Edition, 1997 Garland Publishing Inc., pages 3:1-3:11.see entire selection). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
Artisans are well aware that knowledge of a given antigen (for instance human CD40) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document). Similarly, Lloyd et al. (Protein Engineering Design & Selection 2009, 22;3:159-168) teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding, as their sequencing studies revealed that out of 841 unselected and 5,044 selected antibodies, all but one of the 49 functional VH gene segments was observed (see entire document). Goel et al. (The Journal of Immunology, 2004, 173:7358-7367) disclose the synthesis of three mAbs that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (see entire document). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequence bound in a population of antibodies that bind to a given antigen no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen. Indeed, Kanyavuz et al. (Nature Review Immunology, 2019, 19: 355-368) teach that “Theoretically, under physiological conditions, the human immune system can generate BCRs with 1026 distinct sequences, an astronomical number that is far greater than the calculated number of all B cell clones that can be generated during the lifespan of a healthy human (estimated to be 4 × 1014).
Regarding the claimed method of treating inflammatory bowel disease or symptoms associated with inflammation by administering protein construct that binds TREM1 and IL-23, note that 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).
The claimed method of treating inflammatory bowel disease by administering an a bispecific anti-inflammatory IgG antibody comprising a TREM1 binding VH and VL and an IL-23 binding VH and VL without any structural features including the amino acid sequences of the VL and VL or six CDRs that are required for binding.
The claims do not recite sufficient structural elements, namely the six CDRs from VH and VL that are required for TREM1 and IL-23 binding for the claimed method.
The specification does not provide sufficient guidance and directions such as working examples to enable the full breath of the bispecific IgG antibody which might be able to be used to treat inflammatory bowel disease or treating at least one symptom associated with an inflammatory condition comprises headache, nausea, vomiting, rectal bleeding, diarrhea, and back pain. The claim methods are not limited to the use of a structural defined antibody but rather encompass genus of antibody comprising undefined VH without the VL.
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.
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 is unnecessarily, improperly, and extensive and undue.
Applicant’s arguments in conjunction with the Vemuri declaration have been fully considered but have not been found persuasive.
Applicant argues that the amended claims are not directed to an antibody but a method of treating TREM1 associated inflammation by administering the antibody. Applicant asserts that the specification provides substantial guidance for making and using the recited bispecific anti-inflammatory antibody in [0090], [0098], and [0100]. The specification also discloses how to generate the antibody and how to test for function in Examples 3, 4 and [0210]. The Vemuri declaration states that rejection of IL-17A, IL-1β, and TNFα are achievable using the bispecific anti-inflammatory IgG antibody. Accordingly, applicant asserts that the downstream effect of the bispecific anti-inflammatory IgG antibody that binds TREM1 and IL-23 is associated with binding to both TREM1 and IL-23 is not dependent upon any particular sequences of the TREM1 and IL-23 binding domain. The Vemuri declaration provides data to show that the bispecific anti-inflammatory IgG antibody within the scope of the claims successfully reduced secretion of pro-inflammatory factions including IL-17A, IL-1b, and TNFα by human cells in vitro. Further, applicant asserts that the agonist or antagonist anti-TREM-1 antibody in Pincetic et al. relates to monospecific anti-TREM-1 antibodies in the presence of TREM1 ligand not the bispecific antibody. Applicant asserts that the instant specification provides considerable guidance and direction that enables one of skill in the art to practice the claimed method.
As such, applicant asserts that the rejection should be withdrawn.
This is not found persuasive for following reasons:
The new limitations of “a bispecific anti-inflammatory IgG antibody” and “wherein contacting cells in vitro with the bispecific anti-inflammatory IgG antibody results in a lower secretion of at least one inflammatory biomarker selected from a group consisting of IL-17A, IL-lb and TNFa by the cells as compared to contacting comparable cells with a comparable amount of a corresponding monospecific TREM1 binding antibody, a corresponding monospecific IL-23 binding antibody, or a combination thereof’ recites a general structure of bispecific antibody and its in vitro features but adds nothing that would enable one of skill in art to make and use the claimed bispecific antibody for the recited methods. Without the antibody, one cannot practice the method.
Further, it was known in the art that anti-TREM1 antibody can be agonist or antagonist as disclosed by that Pincetic et al. (US 2025/0092131) as discussed above. There is in sufficient objective evidence in the instant specification, applicant’s REMARK or the Vemuri declaration to show that these two types of anti-TREM1 antibodies having opposite effects would be expected to have the same functions recited in the instant claims. The Vemuri declaration using specific bispecific antibody is not commensurate in scope of the instant claims which are drawn to the use of any or all bispecific antibody that binds TREM1 and IL-23. Further, the Vemuri declaration fails to disclose whether the anti-TREM 1 antibody is agonist or antagonist as they would be expected to have opposite effect.
In vitro and animal model studies have not correlated well with in vivo clinical trial results in patients. It is not clear that reliance on the in vitro evidence of using one bispecific antibody that binds TREM1 and IL-23 in vitro accurately reflects the enablement of the claimed methods relying upon any bispecific anti-inflammatory IgG antibody that binds TREM1 and IL-23.
Therefore, the instant specification fails to provide sufficient guidance and direction to identity and to enable any or all bispecific anti-inflammatory IgG antibody 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 antibody 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 persuasive.
9. 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.
10. 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.
11. Claims 1, 3, 6, and 8-21 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), Yang et al. (US 2021/0061925), and Kontermann et al. (Drug Discovery Today, 2015, 20;7:838-1422) 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 (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 signs 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 to conclude 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]).
Yang et al. teach bispecific antibodies combining specificities of two monospecific antibodies expands the scope of antibody drug development with improved breadth and potency for biotherapeutics for treating complexed disease such as arthritis and inflammatory disorders (e.g. see [0004]). The bispecific antibodies could be differentiated from ‘normal’ antibodies because they had dual functionalities (e.g. see page 838).
Similarly, Kontermann et al. teach bispecific antibodies combine specificities of two antibodies and simultaneously address different antigens or epitope. Bispecific antibodies with two target functionalities can place targets into close proximity, either to support protein complex formation on one cell or to trigger contacts between cells (e.g. see Abstract).
Kontermann et al. teach IgG-like bispecific antibody (e.g. see FIG.1 or copy below):
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Kontermann et al. teach bispecific DVD-Ig directed at receptor ligand and a cytokine can ser as therapeutic for inflammatory disease. For example, both receptor ligand tumor necrosis factor (TNF) and IL-17 were known to contribute to inflammatory disease such as rheumatoid arthritis and monospecific antibodies that target these ligands are readily available. Thus, a bispecific antibody that binds both targets were developed to inactivate both factor. (e.g. see left col. in page 844).
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), and the in vitro features of the bispecific antibody as recited in newly amended independent claims 1, 20, and 21.
Applicant’s arguments in conjunction with the Vemuri declaration have been fully considered but have not been found persuasive.
Applicant asserts that Pincetic et al. teach an anti-TREM1 antibody but do not teach a bispecific anti-TREMxIL23 antibody. Applicant argues Almradi teaches anti-IL-23 antibody for treating inflammatory bowel disease but do not teach a bispecific antibody that binds TREM1 and IL23 for treating inflammatory bowel disease.
Applicant asserts that Yang et al. teach a laundry list of antigens to pick and choose to make the multispecific antibody. As such, applicant argues that a skill in the art would not reach a successful result unless impermissible basis is used to establish the reasonable expectation of success.
The Vemuri declaration discloses on bispecific IgG anti-TREM1xIL-23 antibody tested for their effect on human PBMCs and show that the bispecific antibody can induce a greater decrease in inflammatory biomarkers IL-17A, IL-1b, and TNFα when compared to the combined administration of corresponding monospecific anti-TREM1 antibody and anti-IL-23 antibody which is surprising and unexpected.
As such, applicant asserts that the rejection should be withdrawn.
This is not found persuasive for following reasons:
The results showing in the Vemuri declaration relying upon a single bispecific anti-TREM1xIL-23 antibody in human PBMCs is not commensurate in scope with the instant claims that drawn to a method of treating inflammatory bowel disease by administering a genus of bispecific anti-inflammatory IgG antibody without any structural features (e.g. amino acid sequences for the VH and VL or amino acid sequences for the six CDRs for each of the antigen binding domain).
Further, contrary to applicant assertion of the surprising and unexpected results compared to the combination of two monospecific antibodies, note that any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is truly unexpected. See MPEP 716.02.
Here, given that TREM1 and IL-23 were both validated targets in inflammatory diseases including inflammatory bowel disease as shown by Pincetic et al. and Almradi et al., bispecific antibody that binds both TREM1 and IL-23 simultaneously is expected to generate enhanced efficacy as taught by Yang et al. and Kontermann et al.
Therefore, applicant’s arguments have not been found persuasive.
12. No claim is allowed.
13. 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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/CHUN W DAHLE/Primary Examiner, Art Unit 1641
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