l 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 amendments filed 11/29/2022 are acknowledged. Claims 1-15 are pending and currently under examination.
3. Applicant' s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of PCT/EP2021/064427 filed 05/28/2021, which claims benefit of Foreign application EP20177337.1 filed 05/29/2020. Claims 1-15 have an effective filing date of 05/29/2020.
Claim Objections
4. Claims 2 and 3 are objected to because of the following informalities: these claims recite “the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NOs: 1, 2 (or 10) and 3, respectively”. If applicant intends that HCDR2 may be set forth as SEQ ID NO: 2 or SEQ ID NO: 10, examiner recommends clarifying this limitation. For instance, “the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NOs: 1, 2 and 3, respectively, or the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NOs: 1, 10 and 3, respectively” would be deemed appropriate. Appropriate correction is required.
Claim Rejections - 35 USC § 112
5. 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.
6. Claims 1-3, 5-7, 9 and 15 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 1, recites “with a monovalent dissociation constant (KD) in the range of from 0.5 to 20 nM, in particular in the range of from 0.6 to 10 nM”; the phrase “in particular” renders this claim indefinite because it unclear to the examiner whether the preceding range is part of the claimed invention. Therefore, claim 1 is indefinite for not clearly defining the meets and bounds of the claimed invention.
Claims 2, 5-7 and 15 recite limitations that are qualified by the term “particularly”; this renders these claims indefinite because it is unclear to the examiner whether the limitations preceding this adverb are part of the claimed invention. Therefore claims 2, 5-7 and 15 are indefinite for not clearly defining the meets and bounds of the claimed invention.
Claim 9 recites the term “especially”; this renders this claim indefinite because it is unclear to the examiner whether the limitations preceding those with the qualifying term “especially” are part of the claimed invention. Therefore, claim 9 is indefinite for not clearly defining the meets and bounds of the claimed invention.
Claim 9 recites the limitations, "said first single-chain protein" and “said second single-chain protein”, repeated in every other line of instant claim 9 (e.g., lines 3, 5, 7, 9 etc.). There is insufficient antecedent basis for these limitations in the claim. Therefore, claim 9 is further indefinite for failing to clearly define the meets and bounds of the claimed invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 1 recites the broad recitation “range of from 0.5 to 20 nM”, and the claim also recites “range of from 0.6 to 10 nM” which is the narrower statement of the range/limitation.
Additionally, claim 3 recites “at least 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100” (e.g., see subclaim c.1) in reference to the percent identity for the VH and VL amino acid sequences. These alternative limitations recites the broad recitation “at least 80” and the claim also recites more narrow limitations.
Additionally, claim 5 recites the broad recitation “monovalent KD of 0.5 to 50 nM”, and the claim also recites “1 to 40 nM” and “2 to 35 nM” which are narrower statements of the range/limitation.
Therefore, claims 1, 3 and 5 are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
7. 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.
8. Claims 1-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a multispecific antibody comprising specific amino acid sequences for the six CDRs for MSLN binding and CD3 binding or the specific amino acid sequences for the VH and VL for MSLN binding and VH and VL for CD3 binding, does not reasonably provide enablement for more. 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.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The scope of the claim
Base claim 1 recites, “A multispecific antibody comprising: a) two antibody-based binding domains that is capable of specifically binding to mesothelin (MSLN- BDs) and CD3”. Therefore, this claim represents a genus of "multispecific antibodies". Claims 2 and 3 are dependent on claim 1 and recite structural limitations which define the amino acid sequences for the MSLN binding domain; however, these claims do not recite any such structural limitations of the other claimed binding domain (CD3). Claim 6 is ultimately dependent on claim 1 and recites structural limitations defining the CD3 binding domain, but do not define the MSLN domain. Claim 7 is dependent on claim 1 and recites structural limitations defining an additional hSA binding domain, but does not recite such limitations for an MSLN or CD3 binding domain. Therefore, as claims 2-15 are dependent from Claim 1, and do not materially limit the genus of agents, they are therefore included in the rejection. These claims do not require that the genus of the claims possess any particular structure or other distinguishing feature that is characteristic of the genus as a whole. Since the genus of multispecific antibodies in claims 1-15 do not identify specific structural constraints, the scope potentially encompasses “quintillion” unique species as discussed in In Amgen v. Sanofi, 598 U.S. 594 (2023). Briney et al. (Nature 2019. 566:393-399) was cited in the Supreme Court decision to determine a potential scope of an antibody claim.
The amount of direction provided by the inventor and existence of working examples
In table 1 of the specification (beginning pg. 64), only three MSLN binding domains are defined by specific amino acid sequences which comprise a complete set of six CDRs. These MSLN binding domains are also identified as “54-01-G02”, “54-01-G02 N66A” and “54-32-A07”.
In total, the specification discloses four multispecific antibodies with two binding domains capable of targeting MSLN and one binding domain capable of targeting CD3 (PRO2000, PRO2562, PRO2566 and PRO2567; see table 19, pg. 111 of the specification). Further, according to the specification, the binding affinities reported in table 19 were measured with SPR but were assessed as bi-valent constructs and do not represent the monovalent KD for each domain, as required by the limitation in base claim 1 (e.g., ¶0195). Of the four multispecific antibodies (those reported in table 19), only two of these constructs comprise two anti-MSLN binding domains with a monovalent KD in the claimed range (as reported in table 9 of the specification, pg. 95); these include PRO2000, which comprises two domains of 54-01-G02-sc01, and PRO 2562, which comprises two domains of 54-32-A07-sc09 (see table 17 for architecture of the binding molecules). These two anti-MSLN domains appear to correspond to the specific amino acid sequences comprising a complete set of 6 CDRs as reported in table 1 of the specification (beginning on page 64). Therefore, the scope of the claimed invention is incredibly broad compared to what is disclosed in the specification.
The level of predictability in the art
In Amgen v. Sanofi, 598 U.S. 594 (2023), the Supreme Court held that Amgen was not enabled for “the entire genus” of antibodies that (1) “bind to specific amino acid residues on PCSK9,” and (2) “block PCSK9 from binding to [LDL receptors]” (872 F. 3d 1367, 1372) even though Amgen identified the amino acid sequences of 26 antibodies and disclosed two “trial and error” methods (“the roadmap” and “conservative substitution”) that Amgen insisted scientists could use to make other antibodies that perform these two functions. The case law applies to the instant claims which require a genus of multispecific antibodies, binding specifically to MSLN and CD3, including the limited disclosure of anti-MSNL domains with monovalent KD ranges described in the specification.
At the time of filing, antibody functionality was known to depend on the entire structure, particularly a full complement of six CDRS. It is understood by one of ordinary skill in the art that mutation to CDRs is unpredictable and that each construct requires function testing.
Sela-Culang, Kunik and Ofran (Fron. Immuno., Vol. 4, Article 302, Oct. 2013), hereinafter “Sela Culang”, reviews the structural basis of antibody-antigen recognition in the state of the art. Naturally occurring antibodies typically consists of four polypeptide chains with two identical heavy (H) and two identical light (L) chains, with H and L chains liked to form a Y-shaped structure known as a Fab [e.g., pg. 4, Figure 2A-B]. The Fab has two variable (V) domains (VH and VL) that dimerize to form the Fv fragment which comprises the antigen-binding site of the antibody via six hypervariable loops (3 Heavy, 3 light) [e.g., pg. 3, “The Role of CDRs and their Definition”]. The six hypervariable loops are commonly termed complementary determining regions (CDRs) and are widely assumed to be responsible for antigen recognition [e.g., pg. 1, abstract] and the three-dimensional configuration of these CDRs form the antigen-recognition complex termed a paratope [e.g., pg. 3, “The Role of CDRs and their Definition”]. Despite the integrated effect of CDRs, antibodies can also be considered a modular system , composed of different elements (e.g., Fab, VH, VL) which may bind to an antigen on their own with the smaller fragments retaining affinity and specificity, which is of great potential for drug design [e.g., pg. 6, paragraph 2]. A person of ordinary skill in the art would understand that although the above basics of antibody-antigen binding are known, that the specifics of antibody structure (e.g., within the CDRs) that underlie the antigen recognition are not well characterized [e.g., pg. 1, “The Motivations for…”].
Further, Herold et al. (Nature Scientific Reports, 7:12276, 25 Sep 2017), hereinafter “Herold”, teaches that it should be emphasized that there is no correlation between experimentally determined change in antibody binding affinity and a given mutation and additionally that no such correlation is expected because antigen binding is “affected by each CDR loop differently” and changes thereto “can in principle affect antigen binding affinity in an unpredictable way” [e.g., pg. 14, paragraph 2]. Further, Herold asserts that multiple determinants regulate antigen affinity and the interactions with CDRs are complex [e.g., pg. 14, paragraph 3].
As further evidence, see Koenig et al. (PNAS, E486-E4995, January 5, 2017), which provides a large mutation analysis study where every amino acid in both variable regions are substituted with every other amino acid. In review of figure 1, the bottom half of each section (labeled VEGF) relates to the ability of the mutant to bind the original target, with blue meaning a reduced affinity and black meaning complete loss of binding ability. In VL-CDR1, for example, mutating any given residue to cysteine, which is encompassed by the instant claims (undefined sequence variability up to 3 amino acids or 5% sequence identity, depending on the claim language), resulted in reduced binding at 7 residues and a complete loss of binding (no longer binds same target) at 4 residues. That is, at 100% of positions, mutation to cysteine reduced or ablated the antibody’s ability to bind the target, even in the case of conservative mutations.
Thus, making changes to the CDR sequence of an antibody is a highly unpredictable process and one skilled in the art could not a priori make any predications regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required function(s).
The quantity of experimentation needed to make or use the invention based on the disclosure
Based on the content of the disclosure in view of the recent Supreme Court ruling regarding nature of an antibody invention, a skilled artisan, through extensive trial-and-error experimentation, would have to make antibodies, validate their function. For these reasons, the specification does not enable one of ordinary skill in the art to make and/or use what is claimed and therefore claims 1-15 are rejected under 35 U.S.C. 112(a).
Claim Rejections - 35 USC § 103
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.
10. 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, 4-5, 8, and 10-15 are rejected under 35 U.S.C. 103 as being unpatentable over Austin et al. [Cancer Res (2018) 78 (13_Supplement): 1781] in view of Yoon et al. (Biomolecules. 2020 Mar 4;10(3):399. PMID: 32143496).
Austin et al. teach a tri-specific T cell Activating construct (TriTACs) HPN536 consists of single domain antibodies designed to simultaneously bind to MSLN on tumor cells and to CD3ε on T cells with an affinity of 1nM and 14nM. A third domain of the construct binds to serum albumin to extend serum half-life. Austin et al. teach that TriTACs are much smaller than full size antibodies and have improved penetration of human tumor compared to full sized antibodies. HPN536 is highly stable single polypeptide that can lyse MSLN-positive tumor cells at single-digit picomolar concentration and is well tolerated and showed pharmacokinetics in support of weekly dosing in humans. The reference teachings differ from the instant invention by not describing two binding domains that specifically bind to MSLN.
Yoon et al., in the field of bispecific antibodies, teaches trivalent binding molecules with monovalent specificity for CD3 and bivalent specificity for MSLN (e.g., abstract; pg. 4, ¶1; see also fig 2a). Each of the MSLN binding domains demonstrated a monovalent dissociation constant (Kd) ranging between 0.5 to 20 nM (pg. 8, last ¶; see also table 1, pg. 9).
Austin et al. and Yoon et al. are both directed to multispecific antibodies targeting MSLN and CD3. Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was filed, to modify the TriTACs of Austin et al. with an additional MSLN binding domain taught by Yoon et al. to achieve the predictable result of obtaining a multispecific binding protein with two variable domains specifically binding to MSLN. One of ordinary skill in the art would have been motivated to do so because Yoon et al. teach that the bivalent specificity for MSLN (as demonstrated by MG1122-B) promotes high binding avidity toward tumor cells, and its tumor targeting was superior to that of MG1122-A, which binds monovalently to MSLN (pg. 13, lines 7-9; see also fig 2c-d).
Regarding claims 4-5 and 8, Austin et al. in view of Yoon et al. teach the multispecific antibody of claim 1 (discussed above) and the CD3 binding domain of Austin binds to CD3ε with a binding specificity within the range recited in the instant claims. Further, the multispecific antibody taught by Austin does not comprise CH1 or CL regions (also discussed above). Therefore, claims 4-5 and 8 are obvious over Austin et al., in view of Yoon et al.
Regarding claims 10-15, Austin et al. in view of Yoon et al. teach the multispecific antibody of claim 1 (discussed above). Yoon et al. discloses nucleic acids encoding for multispecific antibody comprised in expression vectors wherein scFab fragments are fused together using (G4S)3 linkers (e.g., methods 2.4, beginning pg. 3). Yoon also discloses host cells (Expi293 cells), transfected with said vectors (e.g., methods section 2.5). Yoon also discloses the use of these transfected cells in a method for producing said multispecific antibody in vitro with said antibodies bsAb being purified from the cell culture supernatant (e.g., methods section 2.5). Austin also discloses how the mesothelin/CD3- specific TriTac was produced by eukaryotic cell culture and secreted as a highly stable, single polypeptide which, in a preclinical characterization study suggested that it was an efficacious and safe novel therapeutic candidate for the convenient treatment of patients with MSLN-expressing malignancies. Therefore, claims 10-15 are obvious over Austin et al., in view of Yoon et al.
Conclusion
12. No claim is allowed.
13. A multispecific antibody comprising two antibody-based binding domains which specifically bind to mesothelin as defined by specific amino acid sequences recited in claim 3 and an antibody-based binding domain which specifically binds to CD3 as defined by specific amino acid sequences recited in claim 6, appears to be free of the prior art.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES L MCLELLAN whose telephone number is (703)756-1906. The examiner can normally be reached Monday - Thursday 7:30 am - 5:30 pm. *Compressed day off on first Friday of each Bi-week.
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, 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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/JAMES LYLE MCLELLAN/Examiner, Art Unit 1641
/CHUN W DAHLE/Primary Examiner, Art Unit 1641
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