DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
1. The Election filed September 16, 2026, in response to the Office Action of June 22, 2026, is acknowledged and has been entered. Applicants elected without traverse the species of the antibody BE-146 and the claimed CEA and CD137 associated amino acid sequences. Claims 1-4, 6-8, 10-16, 18, 27, 30, 32, 34, 47-50 are pending and are currently under prosecution as drawn to the elected species.
Priority
2. Application claims the benefit and priority as a Continuation of PCT/CN2022/093565 filed on 5/18/2022 which claims the benefit and priority of PCT/CN2022/088172 filed on 4/21/2022, PCT/CN2022/085625 filed on 4/7/2022, and PCT/CN2021/095113 filed on 5/21/2021. Application is granted the benefit of PCT/CN2021/095113 and the effective filing date of 5/21/2021.
Claim Rejections - 35 USC § 112
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.
3. Claims 2-4, 6-8, 10-12, 15-16, 18, 27, and 30 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.
Claim 2 is indefinite due to the recitation of “other CEACAM family members”. This limitations is unclear because it does not specify what constitutes a CEACAM family member and the specification provides no definition for an “other” CEACAM family member.
Claims 3, 6-7, 10-12, 15-16, and 18 are indefinite due to their recitations of sequences.
Claims 3, 7, and 11 recite “a [H/L]CDRX of SEQ ID NO: X”, this is indefinite because it is unclear which CDR is being defined and how the CDR is being defined. Examiner suggests re-writing claims 3, 7, and 11 according to the example below of claim 3 to properly define the CDRs of the variable regions:
“The multispecific antibody or antigen-binding fragment thereof of claim 1, wherein the first antigen binding domain that specifically binds to human CEA comprises a heavy chain variable region comprising a HCDR1, HCDR2, and HCDR3, and a light chain variable region comprising a LCDR1, LCDR2, and LCDR3 and is selected from group consisting of:
(i) thethethe amino acid sequence of SEQ ID NO: 7, (b) thethe amino acid sequence of SEQ ID NO:8, and (c) thethe amino acid sequence of SEQ ID NO:9; and thethethe amino acid sequence of SEQ ID NO: 10, (e) thethe amino acid sequence of SEQ ID NO: 11, and (f) thethe amino acid sequence of SEQ ID NO:6;”.
Claims 6, 10, and 12 recite “a [heavy/light] chain variable region that comprise SEQ ID NO: X”, this is indefinite because it is unclear which heavy or light chain is being defined and how it is being defined. Examiner suggests re-writing claims 6, 10, and 12 according to the example below from claim 6 to properly define the heavy and light chain variable regions:
“The multispecific antibody or antigen-binding fragment thereof of claim 1, wherein the first antigen binding domain that specifically binds to human CEA comprises a heavy chain variable region and a light chain variable region selected from the group consisting of:
(i) thethe amino acid sequence of SEQ ID NO:14, and thethe amino acid sequence of SEQ ID NO: 15;”.
Claim 15 recites “comprises a linker selected from SEQ ID NO:317 to SEQ ID NO: 358.”, this is indefinite because it is unclear how the linker is being defined by the SEQ ID NOs. Examiner suggests re-writing the limitation to “comprises a linker selected from the amino acid sequences of SEQ ID NO:317 to SEQ ID NO: 358.”
Claim 16 recites “wherein the linker is SEQ ID NO: 324 or SEQ ID NO: 329.”, this is indefinite because it is unclear how the linker is defined by the sequences. Examiner suggests re-writing the phrase “wherein the linker comprises the amino acid sequences of SEQ ID NO: 324 or SEQ ID NO: 329.”
Claim 18 recites “wherein the bispecific antibody is BE-146 (SEQ ID NO: 313 and SEQ ID NO: 179),” this is indefinite because it is unclear how the sequences are related to the antibody listed. Examiner suggests amending the claims to recite “wherein the bispecific antibody is BE-146 comprising the amino acid sequences of [[(]]SEQ ID NO: 313 and SEQ ID NO: 179[[)]],”
Claims 4 and 8 are rejected based on their dependency on rejected claims but otherwise properly recite the sequences listed.
The term “reduced” and “increased” in claim 27 is a relative term which renders the claim indefinite. The term “reduced” or “increased” 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. Specifically, claim 27 recites the following indefinite limitations:
reduced glycosylation
increased bisecting GlcNac structures
These limitations are indefinite because they imply comparison to a previous result or response but it is unclear what the invention is being “reduced” or “increased” from.
Claim 30 recites the limitation "the Fc domain" in line 2. Claim 1 from which claim 30 depends does not recite a Fc domain. There is insufficient antecedent basis for this limitation in the claim.
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.
4. Claims 1-4, 6-8, 10, 13-16, 27, 30, 32, 34, and 47-50 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. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn to a multispecific antibody or antigen-binding fragment comprising a first antigen binding domain that specifically binds to human CEA at amino acids 596-674 of SEQ ID NO: 88 and a second antigen binding domain that specifically binds to human CD137.
Thus, the claims identify the antibody as being multispecific and binding both human CEA at amino acids 596-674 of SEQ ID NO: 88 and human CD137. Thus, the claims encompass a vast genus of multispecific antibodies comprising variable amino acid sequences that are required to bind human CEA and CD137.
The instant specification discloses the complete amino acid structure of three distinct anti-CEA antibody including the complete variable region comprising three HCDR regions and the light variable region including the three LCDR regions for antibodies BGA113K, BGA190, and BGA288 in Table 1 on pages 35-40.
The instant specification discloses the complete amino acid structure of three distinct anti-CD137 VHH sequences including the heavy variable region comprising the three HCDR regions for antibodies BGA-7207, BGA-4712, and BGA-5623 in Table 2 on pages 40-43.
Thus, the instant specification discloses three distinct antibodies that comprise a heavy chain variable region with distinct CDR regions and a light chain variable region with distinct CDR regions that bind human CEA at the amino acids 596-674 of SEQ ID NO: 88 and three distinct antibodies that comprise a complete heavy chain variable region comprising three distinct CDR regions that function to bind CD137. The specification fails to disclose any other HCDR1, HCDR2, and HCDR3, or LCDR1, LCDR2, and LCDR3 sequence variants that possess the function of binding human CEA at amino acids 596-674 of SEQ ID NO: 88 and human CD137.
To provide adequate written description and evidence of possession of the claimed multispecific antibody genus, the instant specification can structurally describe representative multispecific antibody variants that function to bind human CEA and CD137, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
In this case, the only factor present in the claims is a recitation of the antibody function, “binds to human CEA” and “binds to human CD137”. The instant specification fails to describe structural features common to the members of the multispecific antibody genus, which features constitute a substantial portion of the genus because the instant specification fails to disclose representative antibody variant sequences that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the antibody does, rather than what it is. Other than for the antibodies disclosed in Tables 1 and 2, the specification fails to provide the CDR structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of multispecific antibody sequence variants for the genus of multispecific antibodies that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to make the claimed multispecific antibodies.
The claims broadly encompass any sequence variant that functions to bind human CEA at amino acids 596-674 of SEQ ID NO: 88 and human CD137. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the CDRs that can be altered and still maintain CEA or CD137 binding function. Sela-Culang (Frontiers in Immunol., 2013, 4:302) teaches that antibody CDRs have a unique set of contact preferences, favoring certain amino acids over others. (See Sela-Culang, pgs. 5-6). Given the well-known high level of polymorphism of antibody CDR sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of multispecific antibodies encompassed by the claimed invention. One could not reasonably or predictably extrapolate the structure of a single multispecific antibody to the structure of any variants required to bind human CEA and human CD137 as broadly claimed. Therefore, one could not readily envision members of the broadly claimed genus.
Although Applicants may argue that it is possible to screen for antibodies that bind CEA and CD137 and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies yet to be discovered that may function as claimed. The CEA and CD137 antigen provides no information about the structure of an antibody that binds to it.
Given the lack of representative examples to support the full scope of the claimed variant multispecific antibodies, and lack of reasonable structure-function correlation with regards to the unknown variable sequences in the CDRs that provide CEA and CD137 binding function, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of multispecific antibody variants that bind CEA and CD137 that is required to practice the claimed invention.
Examiner Suggestion: Examiner suggests amending claim 1 to recite the claim limitations of claims 3 and 7 to overcome the written description rejection.
5. Claims 11-12 and 18 are not included in the above rejection because the claims as written incorporate the amino acid structure of both the anti-CEA and anti-CD137 antibodies.
6. Claim 34 is 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 treating CEA+ cancer, does not reasonably provide enablement for the treatment of all cancers. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
The claims are drawn to a method for treating cancer by administering a multispecific antibody that binds human CEA and human CD137.
Thus, the breadth of the claims are directed to treating any type of cancer using an antibody that specifically binds to human CEA and human CD137. As discussed below, the specification does not support the antibody treating any type of cancer as broadly claimed.
The specification discloses the antibody’s ability to specifically bind to both CEA and CD137 through in vitro studies (Example 30). In vivo studies used to assess efficacy of the antibodies only used CEA expressing tumor cell lines (Examples 14, 28, 37). Examples 31 and 33 directly indicate the induction of activity by the CD137 antibody is dependent on CEA binding.
Thus, the direction and guidance from the specification indicates that for the antibody to be effective, the antibody must bind to CEA first before CD137 can activate the immune cells.
The working examples provide ample evidence that the antibodies are directed to bind only CEA and CD137 and efficacy of the antibody was only demonstrated in the presence of tumor cells expressing CEA.
Relevant art teaches CEA expression in certain cancers, for example those of epithelial origin, are known to be highly expressed but other cancers show low to no expression of CEA. (Hammarstrom, Cancer Biology, 1999, 9:67-81 as cited in IDS from 1/27/2026; see pg. 74, “Expression of CEA family members in tumors” also Table 2).
PNG
media_image1.png
492
672
media_image1.png
Greyscale
Thus, the nature of the invention requires CEA to be expressed on the cancer it is being used to treat. As Hammerstrom and Table 2 evidence above there is a high degree of unpredictability in knowing whether any given cancer type will express CEA or not. For example, breast carcinoma and serous ovarian carcinoma only demonstrate 10-50% CEA expression, while other cancers demonstrated absolutely no expression of CEA for example hepatocellular carcinoma. Thus, the nature of the invention requires undue experimentation to treat all cancers when not all cancers express CEA.
The state of the prior art, as evidence by Hammarstrom provides that while it is well known that CEA is highly expressed in certain cancers, not all cancers express CEA. A skilled artisan would not be aware of how to treat a CEA- cancer using the present claimed invention.
The relative skill of those in the art would require highly specialized skills to use an antibody that binds CEA in a cancer not expressing CEA. The ordinary skilled artisan would require undue experimentation to practice using the antibody binding CEA and CD137 to treat a cancer that does not express CEA as broadly claimed.
The unpredictability of the art is high as demonstrated by Table 2 from Hammarstrom. Certain cancers are known to express high levels of CEA, while others have low or no expression of CEA meaning some cancer patients could benefit from the treatment while others would not.
The quantity of experimentation necessary to enable the antibody to treat any type of cancer would require extensive experimentation to determine how CEA- cancers could benefit. If a benefit was found, it would then require additional experimentation to prove the therapy effective for the various types of cancer that exist.
One cannot extrapolate the disclosure of the specification to the scope of the claims because the claims broadly encompass treating all cancer types with an antibody that specifically targets the tumor antigen CEA, the specification provides guidance and examples that indicate the antibody is only useful in the context of a CEA+ cancer, and relevant art teaches that not all cancer express CEA.
Reasonable correlation must exist between the scope of the claims and scope of enablement set forth, and it cannot be reasonably predicted that the multispecific antibody that binds CEA and CD137 will predictably function as claimed.
Therefore, in view of the novel nature of the invention, what is unknown in the art because of the novel nature of the invention, the state of the art, the quantity of experimentation necessary, the breadth of the claims, lack of guidance in the specification, and the absence of working examples, it would require undue experimentation for one skilled in the art to practice the invention as broadly claimed.
Examiner Suggestion: Amend claim 34 to recite “A method of treating CEA+ cancer…”
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
7. Claims 1-2, 13-14, 27, 30, 32, 34, and 47-50 are rejected under 35 U.S.C. 103 as being unpatentable over Mikkelsen, et al. (Frontiers in Immunol., 2019, 10:1791) in view of Decary et al. (Clin Cancer Res., 2020, 26:6589-99).
Mikkelsen discloses a bispecific antibody comprising a first antigen binding domain that specifically binds to human CEA and a second antigen binding domain that specifically binds to human CD137 (4-1BB) for the treatment of cancer. (See Mikkelsen, abstract).
Regarding claim 27, Mikkelsen discloses that the CEA/CD137 bispecific antibody was successful at stimulating antibody dependent cellular cytotoxicity. (See Mikkelsen, pg. 8 column 2 lines 4-6).
Regarding claim 30, Mikkelsen discloses the bispecific antibody has a construct with reduced IgG1 effector functions. (See Mikkelsen, pg. 8 column 2 line 10- pg. 9 column 1 line 5).
Regarding claims 32 and 47-50, Mikkelsen discloses the bispecific antibodies being produced by recombinant technology including introducing an isolated nucleic acid into an expression vector that is expressed through a host cell and a pharmaceutical composition comprising the bispecific antibody in a pharmaceutically acceptable carrier. (See Mikkelsen, pg. 2 column 2 line 24- pg. 3 column 1 line 8).
Mikkelsen does not disclose the antigen binding domain that specifically binds to human CEA at amino acids 596-674 of SEQ ID NO:88 and does not bind to other CEACAM family members.
Decary discloses a CEA antibody in the form of a monoclonal antibody and an antibody-drug conjugate that successfully binds to human and cynomolgus monkey CEACAM5 (See Decary, abstract) but demonstrated no binding to human or cynomolgus monkey CEACAM1, CEACAM6, or CEACAM8 (See Decary, pg. 6593 column 2 lines 1-7). Decary also teaches that CEACAM5 is a cancer target due to limited expression in normal adult cells but overexpression in multiple forms of cancers but other CEACAM family members are expressed on normal healthy cells. (See Mikkelsen, abstract and pg. 6590 column 1, lines 20-24).
Decary does not disclose the CEA antibody binds specifically to the amino acids represented by positions 596-674 of SEQ ID NO: 88 of the present application. However, Decary does teach the CEACAM family members share 85.7% sequence similarity in the extracellular domains of their identity. This suggests that the sequence required to maintain binding for CEACAM5 while avoiding binding to other CEACAM family members must be significantly similar to each other.
It would have been prima facie obvious for a person of ordinary skill in the art prior to the effective filing date to use the CEA and CD137 bispecific antibody of Mikkelsen using the CEA antibody of Decary to produce the present claimed invention. It would have been obvious because the bispecific antibody of Mikkelsen was making other transformations to reduce off-target cytotoxic effects like reducing the IgG effector functions and Decary teaches that targeting CEACAM5 while avoiding binding to other CEACAM family members would make an attractive cancer targeting antibody. It has a reasonable expectation of success because both Mikkelson and Decary had successfully tested a version of an antibody for CEA and CD137, and for the CEACAM5-specific antibody, respectively. It would have been obvious to a person of ordinary skill in the art to select an epitope within CEA that is sufficiently divergent from other CEACAMs in order to achieve the desired specificity, as routine sequence alignment and epitope mapping techniques were well known in the art. Thus, the selection of residues 596–674 as the epitope for CEA binding represents an obvious choice for achieving specificity, especially in view of the motivation to avoid off-target effects and the routine nature of epitope mapping in antibody development. Therefore, it would have been obvious to a person of ordinary skill prior to the effective filing date to combine Mikkelson’s bispecific antibody and the CEACAM5-specific antibody of Decary with a reasonable expectation of success at producing the presently claimed CEA and CD137 multispecific antibody.
Conclusion
8. Claims 1-4, 6-8, 10-16, 18, 27, 30, 32, 34, and 47-50 are rejected.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LINDSAY DUNN whose telephone number is (571)272-5825. The examiner can normally be reached Monday-Friday 8-4:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/LINDSAY DUNN/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
Prosecution Insights