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 .
Application Status
The amended claims filed December 22, 2025 with the Response to the non-final Office Action are acknowledged. Claims 32-33, 35-36, 42, and 45-46 are canceled. Claims 31, 34, 37-38, and 43-44 are amended. Claims 47-49 are newly added.
Claims 31, 34, 37-41, 43-44, and 47-49 are pending and under examination herein.
It is noted that the scanned copy of Exhibit B, provided by Applicant with the Response filed December 22, 2025, is difficult to read, particularly with respect to data tables and figures.
Objections to the Specification Withdrawn
The objection to the specification is withdrawn in view of Applicant's amendments thereto.
Claim Objections and Rejections Withdrawn
All prior objections and/or rejections of claims 32-33, 35-36, 42, and 45-46 are rendered moot by the cancelation of the claims.
The rejections of claims 31, 34, 37-41, and 43-44 under 35 U.S.C. § 103 as being unpatentable over Throsby (US 2018/0312604 A1) in view of Hendrikx (The Oncologist (2017) 22(10): 1212-1221), and further in view of Hallin (Cancer Discovery (2020) 10(1): 54-71) or Kim (Biologics: Targets and Therapy (2008) 2(2): 223-228) or Sartore-Bianchi (The Oncologist (2019) 24(10): 1395-1402), are withdrawn in view of Applicant's amendments to claim 31.
The non-statutory double patenting rejections of claims 31, 34, 37-41, and 43-44 over U.S. Patent No. 11,939,394 in view of the secondary references of record are withdrawn in view of Applicant's amendments to claim 31.
The provisional non-statutory double patenting rejections of claims 31, 34, 37-41, and 43-44 over U.S. Patent Application Nos. 17/632,181, 18/257,528, 18/268,168, 18/431,642, 18/694,252, and 19/142,031 in view of the secondary references of record are withdrawn in view of Applicant's amendments to claim 31.
NEW OBJECTIONS AND REJECTIONS NECESSITATED BY CLAIM AMENDMENT
Claim Objections
Claim 31 is objected to for the following informalities: As amended, the claim ends with two periods. Each claim should end with a single period. See MPEP § 608.01(m).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claim 31, 34, 37-41, 43-44, and 47-49 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. This is a new rejection necessitated by claim amendment.
Claim 31 as amended recites a method of treating cancer, wherein the bispecific antibody administered in the method comprises a first antigen-binding site that binds to an extracellular part of EGFR and a second antigen-binding site that binds to LGR5, wherein:
the first antigen-binding site comprises at least the CDR1, CDR2, and CDR3 sequences of “the heavy chain variable region MF3755 (SEQ ID NO: 89)”,
the second antigen-binding site comprises at least the CDR1, CDR2, and CDR3 sequences of “the heavy chain variable region MF5816 (SEQ ID NO: 107)”, and
wherein the bispecific antibody “comprises the CDR1, CDR2, and CDR3 sequences of a common light chain comprising SEQ ID NO: 133”. Claim 47 further recites that the bispecific antibody comprises a first antigen-binding site that comprises “the heavy chain variable region MF3755 (SEQ ID NO: 89)”, a second antigen-binding site that comprises “the heavy chain variable region MF5816 (SEQ ID NO: 107)”, and a common light chain comprising SEQ ID NO: 133.
These limitations are indefinite in part because the sequences recited in the claim (underlined above) do not correspond to the anti-EGFR heavy chain variable region (VH) “MF3755”, the anti-LGR5 VH “MF5816”, and a common light chain, respectively, as set forth in the claim, based on the teachings of Applicant's disclosure:
As shown in Figure 3A, the MF3755 VH comprises the amino acid sequence of SEQ ID NO: 4, not SEQ ID NO: 89 as claimed. SEQ ID NO: 89 appears to correspond to the heavy chain CDR2 of MF5816 (anti-LGR5 antibody) (see Figure 3B).
As shown in Figure 3A, the MF5816 VH comprises the amino acid sequence of SEQ ID NO: 13, not SEQ ID NO: 107 as claimed. SEQ ID NO: 107 appears to correspond to the nucleotide sequence of a VH denoted as “MF1337” (see Figure 3C), the specificity of which is not immediately apparent from Applicant's disclosure.
As shown in Figure 4A, the common light chain recited in the disclosure has an amino acid sequence of SEQ ID NO: 121, not SEQ ID NO: 133 as claimed. The amino acid sequence of SEQ ID NO: 133 corresponds to a hinge region (see Figure 5B).
Accordingly, it is unclear how the instantly claimed bispecific antibody may comprise the CDRs of these respective sequences, which do not correspond to the structural elements recited in the claim and each of which do not comprise three CDRs. In addition, it is noted that the use of parentheses in these claims also renders them indefinite because it is unclear whether the phrase in parentheses is intended to be limiting or merely exemplary.
In a second aspect, claim 31 is indefinite because the claim recites that the antigen-binding sites comprise at least “the CDR1, CDR2, and CDR3 of” a particular VH or light chain amino acid sequence, but the claim does not also articulate a numbering scheme (e.g., EU index, Kabat, Chothia) for determining the locations of the respective CDRs in the claimed VH or light chain sequences. The specification does not provide additional guidance with respect to how to determine the corresponding CDR1, CDR2, and CDR3 sequences of an antibody variable domain based on any known numbering scheme in the art. Accordingly, the claim is indefinite at least because one of ordinary skill in the art cannot determine the intended scope of the claims based on the information presented in the claims or in light of the specification.
Claims 34, 37-41, 43-44, and 47-49, which depend from claim 31 and do not remedy these deficiencies, are similarly rejected.
Claim Rejections - 35 USC § 112(a)
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.
Claims 31, 34, 37-41, 43-44, and 47-49 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 maintained rejection has been updated to reflect Applicant's claim amendments.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991).
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or it may be satisfied by the disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
The claimed invention. The nature and scope of the claimed invention at issue is a method of treating a cancer (as set forth in claim 31 and its dependent claims) wherein the bispecific antibody administered in the method comprises a first antigen-binding site that binds to an extracellular part of EGFR and a second antigen-binding site that binds to LGR5, wherein:
the first antigen-binding site comprises at least the CDR1, CDR2, and CDR3 sequences of “the heavy chain variable region MF3755 (SEQ ID NO: 89)”,
the second antigen-binding site comprises at least the CDR1, CDR2, and CDR3 sequences of “the heavy chain variable region MF5816 (SEQ ID NO: 107)”, and
wherein the bispecific antibody “comprises the CDR1, CDR2, and CDR3 sequences of a common light chain comprising SEQ ID NO: 133”. Claim 47 further recites that the bispecific antibody comprises a first antigen-binding site that comprises the heavy chain variable region MF3755 (SEQ ID NO: 89), a second antigen-binding site that comprises the heavy chain variable region MF5816 (SEQ ID NO: 107), and a common light chain comprising SEQ ID NO: 133. In view of the fact pattern presented in the 35 U.S.C. § 112(b) above, these claim limitations fail to satisfy the written description requirement because the bispecific antibody recited in the claim does not possess a complete structure that would be expected to correlate with the claimed binding activities based on what is understood by those of ordinary skill in the art and in light of Applicant's disclosure.
In order to comply with the written description requirement, the instantly claimed bispecific antibody must comprise a first antigen-binding site that expressly comprises three defined heavy chain CDRs and three defined light chain CDRs, and a second antigen-binding site that expressly comprises three defined heavy chain CDRs and three defined light chain CDRs.
The dependent claims do not remedy this deficiency and are similarly rejected.
State of the prior art. It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) that provide the majority of the contact residues for the binding of the antibody to its target epitope. See Almagro (Frontiers in Immunology (2018) 8: 1751; cited in PTO-892 mailed September 11, 2025), “The IgG Molecule” (page 3) and Figure 1. Sela-Culang (Frontiers in Immunology (2013) 4: 302; cited in PTO-892 mailed September 11, 2025) further teaches, “A major focus in analyzing the structural basis for [antigen] recognition has been in identifying the exact boundaries of the CDRs in a given [antibody]. It is a common practice to identify paratopes through the identification of CDRs” (page 3). Although the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. Ni (The Protein Journal (2024) 43: 683-696; cited in PTO-892 mailed September 11, 2025) teaches, “Mutations, even one mutation, introduced in the CDRs through [somatic hypermutation] can change the binding properties and repertoire of antibodies. However, how just one-point mutation can dramatically change the recognition profiles of the antibody is still unclear” (Introduction). Furthermore, while affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody, those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori (Almagro, pages 3 and 6-7).
Gershoni (Biodrugs (2007) 21(3): 145-156; cited in PTO-892 mailed September 11, 2025) teaches that antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (page 146, Section 1.1). The skilled artisan therefore understands that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence. Further, the state of the art recognizes that it is not possible to predict the amino acid sequence when an epitope is recited, because there are many different epitope arrangements (e.g., linear and discontinuous epitopes) that are dictated by the unique interaction between an antibody and its cognate epitope (Blythe, Protein Science (2005) 14:246-248, at page 246; cited in PTO-892 mailed September 11, 2025).
Bispecific antibodies that specifically target EGFR (also called ErbB-1 or HER-1) and/or LGR5 have previously been disclosed in the art, each comprising a completely structurally defined VH and VL. See, e.g., Kirshner (US 2015/0259423 A1; cited in PTO-892 mailed September 11, 2025); Wong (US 9,090,693 B2; cited in PTO-892 mailed September 11, 2025); van de Winkel (US 2003/0194403 A1; cited in PTO-892 mailed September 11, 2025); Reyes (US 2015/0037324 A1; cited in PTO-892 mailed September 11, 2025); Throsby (US 2018/0312604 A1; cited in PTO-892 mailed September 11, 2025); and Valamehr (US 2021/0015859 A1; cited in PTO-892 mailed September 11, 2025).
Scope of species disclosed in original specification. In the Examples, the disclosure states that the “MF” antibodies described therein (including bispecific antibodies) comprise a VH, a heavy chain constant region, a VL, and a light chain constant region (e.g., page 46). The VL of the antibody typically has an amino acid sequence of SEQ ID NO: 122 (as set forth in Figure 4b) and a light chain amino acid sequence of SEQ ID NO: 121 (as set forth in Figure 4a) (page 46). The MF3755 x MF5816 bispecific antibody comprises an anti-EGFR variable domain comprising a MF3755 VH comprising the amino acid sequence of SEQ ID NO: 4 (as set forth in Figure 3a), an anti-LGR5 variable domain comprising a MF5816 VH comprising the amino acid sequence of SEQ ID NO: 13 (as set forth in Figure 3a), and a common light chain, as well as modifications for enhanced ADCC from afucosylation (pages 46-47). Mutations can be introduced in the CH3 regions of the first and second heavy chains (at positions 351 and 366 and at positions 351 and 368, respectively) to produce essentially only bispecific full length IgG molecules (page 47). Several bispecific antibodies (e.g., MF3370 x MF5790, MF3755 x MF5790, etc.) recited on pages 48-49 are noted as being suitable for use in the methods of the invention, and the disclosure states that “each bispecific antibody comprises two VH as specified by the MF numbers capable of binding EGFR and LGR5 respectively, further comprises an Fc tail with a KK/DE CH3 heterodimerization domain as indicated by SEQ ID NO: 136 (Figure 5d) and SEQ ID NO: 138 (Figure 5e), respectively, a CH2 domain as indicated by SEQ ID NO: 134 (Figure 5c) and a CH1 domain as indicated by SEQ ID NO: 131 (Figure 5a), a common light chain as indicated by SEQ ID NO: 121 (Figure 4).”
In Example 1, a set of esophageal and gastric cancer patient-derived xenograft (PDX) models was used to test the efficacy of an MF3755 x MF5816 bispecific antibody (pages 49-51, Table 1). Intraperitoneal administration of a flat dose of 0.5 mg of the MF3755 x MF5816 bispecific antibody to mice once per week reduced tumor growth in six of the tested gastric PDX models (Figure 6a) and all four of the tested esophageal PDX models (Figure 6b) (Example 1, page 52). Example 2 describes a phase 1 open-label multi-center study in which flat doses of 5 mg (starting), 20 mg, 50 mg, 90 mg, 150 mg, 225 mg, 335 mg, 500 mg, 750 mg, 1100 mg and 1500 mg of an anti-EGFR/anti-LGR5 bispecific antibody were investigated for their safety and preliminary anti-tumor activity in human patients (pages 52-53).
MPEP § 2163 states that 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. In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
As presently amended, the claims do not recite a sufficient level of structure (i.e., three completely defined heavy chain CDRs and three completely defined light chain CDRs) for each antigen-binding site of the bispecific antibody administered in the instantly claimed method. With respect to the EGFR binding site, the amino acid sequence of SEQ ID NO: 89 corresponds to a heavy chain CDR2 from an antibody clone having specificity for a different antigen; this sequence does not comprise three heavy chain CDRs specific for EGFR. Further, the claims do not expressly recite that said EGFR binding site comprises three light chain CDRs, and the hinge region corresponding to SEQ ID NO: 133 does not comprise three light chain CDRs. With respect to the LGR5 binding site, the nucleotide sequence of SEQ ID NO: 107 does not appear to comprise three CDRs that one of ordinary skill in the art would understand to have specificity for LGR5 based on Applicant's disclosure. Based on the teachings of Geuijen (WO 2018/056821 A1), MF1337 appears to correspond to an antibody having specificity for tetanus toxin (e.g., page 147), not LGR5. Further, the claims do not expressly recite that said LGR5 binding site comprises three light chain CDRs, and the hinge region corresponding to SEQ ID NO: 133 does not comprise three light chain CDRs.
Conclusion. For the reasons presented above, one of skill in the art would not be able to determine the specific and complete structure of the instantly claimed bispecific antibody (as recited in claim 31 and its dependent claims) that possesses the required functional activity of binding to an extracellular part of EGFR and to an extracellular part of LGR5.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643