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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 August 13, 2026 has been entered.
Application Status
The amended claims filed August 13, 2026 with the Request for Continued Examination are acknowledged. Claims 1, 3-6, 8, 13-16, 18-20, and 22 are pending. Claims 1 and 6 have been amended. Claim 20 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1, 3-6, 8, 13-16, 18-19, and 22 are under examination herein.
WITHDRAWN OBJECTIONS
The objection to the specification is withdrawn in view of Applicant's amendments to the description for Figure 2.
The objection to claim 6 is withdrawn in view of Applicant's claim amendments thereto.
MAINTAINED REJECTIONS AND NEW OBJECTIONS AND REJECTIONS NECESSITATED BY CLAIM AMENDMENT
Claim Objections (New)
Claims 13-16 and 18-19 are objected to because of the following informalities: Claim 13 ends with a comma followed by a period, with no text in between. The comma could be removed for clarity.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) (New)
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.
Claims 1, 3-6, 8, 13-16, 18-19, and 22 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.
Claim 1 recites the limitation that the pharmaceutical composition or kit comprises “a second HER2 inhibitor”. However, the claim does not earlier recite that the pharmaceutical composition or kit comprises “a first HER2 inhibitor”. Based on the present claim construction, it is not expressly clear what “first HER2 inhibitor” is comprised in the pharmaceutical composition or kit recited in the claim.
Claims 3-6, 8, and 22, which depend from claim 1 and do not remedy this deficiency, are similarly rejected.
Claim 13 recites the limitation that “at least one second HER2 inhibitor” is co-administered in a method of treatment with an anti-HER2 monoclonal antibody. However, the claim does not earlier recite that the method comprises administering “a first HER2 inhibitor”. Based on the present claim construction, it is not expressly clear what “first HER2 inhibitor” is administered in the method of treatment recited in the claim.
Claims 14-16 and 18-19, which depend from claim 13 and do not remedy this deficiency, 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 1, 3-5, 8, and 22 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 new rejection necessitated by claim amendment.
“[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).
Amgen Inc. v. Sanofi, Aventisub LLC, 872 F.3d 1367 (Fed. Cir. 2017) supported previous decisions (Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341 (Fed. Cir. 2011); AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285 (Fed. Cir. 2014)) that defining an antibody solely by what it binds does not satisfy the written description requirement, stating that this would allow patentees to “claim antibodies by describing something that is not the invention, i.e., the antigen”. Thus, claiming an antibody by describing the invention by what it does (function) rather than what it is (structure) is invalid. This can be overcome if a relevant number of species with structure/function correlation is known to the art or present in the specification.
The claimed invention. The nature and scope of the claimed invention at issue is a pharmaceutical composition or kit comprising (1) a monoclonal anti-HER2 antibody or a functional fragment or derivative thereof and (2) a second HER2 inhibitor as recited in claim 1 and its dependent claims, wherein the second HER2 inhibitor is “an antibody that binds to a different epitope than the anti-HER2 antibody”. This limitation fails to satisfy the written description requirement because the second HER2 inhibitor (antibody) is defined by its functional activity (i.e., binding to a “different epitope” than the first-recited anti-HER2 antibody) without reciting a corresponding structure that would be expected to correlate with the claimed functional property based on what it is understood by those skilled in the relevant art and in view of the teachings of the instant disclosure.
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) at “The IgG Molecule” (page 3) and Figure 1. Sela-Culang (Frontiers in Immunology (2013) 4: 302; cited in PTO-892) 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, left column, “CDRs Identification”).
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) 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 unpredictable to those of ordinary skill in the art (Almagro, pages 3 and 6-7).
Gershoni (Biodrugs (2007) 21(3): 145-156; cited in PTO-892) 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, such as linear and discontinuous epitopes, that are dictated by the unique interaction between an antibody and its cognate epitope. See Blythe (Protein Science (2005) 14: 246-248; cited in PTO-892) at page 246.
Many antibodies that target HER2 and use thereof in treating various cancers and tumors are known in the art, including trastuzumab, pertuzumab, T-DM1, afatinib, and lapatinib, as reviewed by Parakh (Cancer Treatment Reviews (2017) 59: 1-21; cited in PTO-892). All of these are conventional antibodies comprising 6 distinct CDR sequences. Parakh teaches that trastuzumab binds domain IV of the extracellular domain of HER2 (e.g., pages 2 and 5, bridging text) and that pertuzumab binds domain II of the extracellular domain of HER2 (e.g., page 6, left column). Harding (US 2011/0177095 A1) discloses the heavy chain and light chain CDRs of trastuzumab (e.g., Tables 1-2; Figures 1A-1C; ¶ 0015). Gennaro (US 2014/0308277 A1) discloses the heavy chain and light chain CDRs of pertuzumab (“2C4”) (e.g., Figures 3A-3B; ¶ 0026).
Scope of species disclosed in original specification. The disclosure recites that the pharmaceutical compositions of the invention comprise an anti-HER2 antibody, comprising a heavy chain comprising a combination of CDRs comprising the amino acid sequences of SEQ ID NO: 1-3, respectively (Table 1, page 5) and a light chain comprising a combination of CDRs comprising SEQ ID NO: 4-6, respectively, or 4-5 and 7, respectively (Table 2, page 5), in combination with a “second HER2 inhibitor” (e.g., pages 1-6). In aspects of the invention, said second HER2 inhibitor is pertuzumab or trastuzumab (e.g., page 1 or 6). The working examples and Drawings disclose a specific embodiment in which MAB270 (which comprises the heavy chain CDRs corresponding to SEQ ID NOs: 1-3, respectively and the light chain CDRs corresponding to SEQ ID NOs: 4, 5, and 7, respectively) is combined with trastuzumab (e.g., Example 2; Figures 2-4).
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.
Applicant's disclosure recites a limited number of exemplary second HER2 inhibitors corresponding to an antibody that binds to a different epitope than MAB270, specifically, trastuzumab and pertuzumab. Although the specific structures (i.e., amino acid sequences) of trastuzumab and pertuzumab are not expressly disclosed by Applicant, these structures are known in the art. See Harding (US 2011/0177095 A1; supra) and Gennaro (US 2014/0308277 A1; supra), respectively. It is understood by those of skill in the art that the minimum structure required for antibody binding to the epitope of an antigen is the three heavy chain and three light chain CDRs in a conventional immunoglobulin. Applicant's disclosure does not provide sufficient written description for additional “second HER2 inhibitors” that are antibodies and that possess the required functional activity of “binding to a different epitope than the anti-HER2 antibody” recited in claim 1.
Conclusion. For all of the reasons presented above, one of skill in the art would not know which of the countless other “second HER2 inhibitor” antibodies encompassed by the highly general structural requirements of the claims would also possess the required functional activity of binding to human HER2 at a different epitope than the first mentioned anti-HER2 antibody recited in claim 1. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, the Applicant did not possess the full genus of “second HER2 inhibitors” as broadly claimed at the time the application was filed.
Claim Rejections - 35 USC § 103 (Maintained)
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.
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.
(1)
Claims 1, 3-6, 8, 13-16, and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Fischer (WO 2017/191327 A2; cited in IDS) in view of Lee (EP 2998319 A1; cited in IDS).
Fischer discloses antibodies or antigen-binding fragments thereof that specifically bind to HER2 at a different epitope than trastuzumab as well as pharmaceutical compositions comprising the same (e.g., page 3). In one embodiment, a humanized anti-HER2 antibody of the invention denoted “B100” comprises a VH comprising the amino acid sequence of SEQ ID NO: 4 (which shares 100% identity to the instantly claimed VH comprising SEQ ID NO: 80, with its corresponding CDRs and FRs) and a VL comprising the amino acid sequence of SEQ ID NO: 10 (which shares 100% identity to the instantly claimed VL comprising SEQ ID NO: 89, with its corresponding CDRs and FRs) (e.g., pages 14-16; Figures, pages 1-2), relevant to claims 1 and 3-5. See sequence alignments between Fischer (Qy) and the instant application (Db) below:
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Fischer teaches that the antibodies of the invention have favorable properties including increased induction of FcR-mediated signaling activity and the capability of inducing apoptosis with an efficacy similar to a cytotoxic drug like camptothecin (e.g., pages 19-22). Fischer teaches that the latter quality “will be additive to the activity of other HER2 antibodies with different modes of action” (page 22, lines 14-24).
Relevant to claims 13-14 and 18-19, Fischer further discloses a method of treating a HER2-mediated disease (e.g., breast cancer, pancreatic cancer, or colon cancer) in a patient which comprises administering a pharmaceutical composition comprising an antibody according to the invention to the patient (e.g., page 2, Summary of invention; page 26).
Fischer further teaches that there is a need for the development of novel, more effective antibodies that can be used in follow-up therapies when clinical results with trastuzumab and chemotherapy are unsatisfying or as an alternative in combination with existing antibodies such as trastuzumab (e.g., page 3, Background).
However, Fischer does not expressly teach a pharmaceutical composition comprising antibody B100 further in combination with a second HER2 inhibitor (e.g., trastuzumab), nor a method of treating a HER2-positive cancer by administering a pharmaceutical composition comprising such a combination.
Lee teaches that although trastuzumab is the most commercially successful anti-HER2 antibody, it only shows therapeutic efficacy in 15% of breast cancer patients overexpressing HER2 (e.g., ¶ 0006-0007). Accordingly, efforts have centered on improving the prognosis of non-responsive or poorly responsive HER2-positive cancer patients by combination therapy, e.g., with the anti-HER2 antibodies trastuzumab and pertuzumab (e.g., ¶ 0007-0009), relevant to claims 15-16. Lee discloses anti-HER2 antibodies and pharmaceutical compositions comprising the same which specifically bind to HER2 at an epitope different from trastuzumab, and which are administered in combination with trastuzumab to overcome limitations associated with trastuzumab monotherapy (e.g., Abstract; ¶ 0011-0017, 0081-0087), relevant to claim 6. Lee shows that the combination of the humanized antibody of the invention “hz1E11” and trastuzumab more strongly inhibits the proliferation of the NCI-N87 and OE-19 cancer cell lines when compared to monotherapy with trastuzumab or hz1E11 (e.g., Figure 8) and dose-dependently decreases tumor cell growth in an NCI-N87 xenograft animal model to a greater extent than trastuzumab monotherapy (e.g., Figure 9). The hz1E11 antibody, alone and in combination with trastuzumab, also more potently induces apoptosis of cancer cells than trastuzumab monotherapy (e.g., Figure 5).
Lee further discloses a kit comprising an anti-HER2 antibody of the invention (e.g., ¶ 0093-0097).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to make and use a pharmaceutical composition comprising the combination of trastuzumab and a second anti-HER2 antibody, e.g., the B100 antibody taught by Fischer, in a method of treating a HER2-positive cancer, based on the collective teachings of Fischer and Lee. The skilled artisan would have been motivated to do so because, as taught by Lee, many patients with HER2-positive cancer do not respond to trastuzumab monotherapy, and a combinatorial treatment comprising two anti-HER2 antibodies that each bind a separate epitope of HER2 is more effective than either antibody alone. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-HER2 antibodies taught by Fischer (B100) and Lee (hz1E11) are functional equivalents in that both possess the same qualities of (1) binding specifically to HER2 at a different epitope than trastuzumab, and (2) potently inducing apoptosis of cancer cells. Accordingly, it would have been obvious to try substituting hz1E11 with B100 in a HER2 combination therapy.
Response to Arguments
Applicant's arguments filed August 13, 2026 have been fully considered but they are not persuasive.
Applicant traverses the rejection on the basis that Fisher nor Lee do not account for all the limitations of claim 1 and its dependent claims. Applicant submits that Fischer does not teach or suggest the combination of the B100 antibody (as the first anti-HER2 antibody used in the present application) with another HER2 inhibitor, and that Lee does not disclose a combination of HER2 antibodies that bind to different subdomains of HER2, as both hz1E11 and trastuzumab bind to subdomain IV of the extracellular domain (ECD) of HER2. Applicant submits that “there was no knowledge in the art that combining any two antibodies that bind different epitopes would be beneficial” and that the combination of trastuzumab and pertuzumab do not have an additive or synergistic effect because an increase in ADCC efficiency isn’t observed when both are combined. Remarks at pages 10-11.
In response to Applicant's arguments with respect to the teachings of the cited references, it is held that the combined teachings of Fischer and Lee still account for the combination of an anti-HER2 antibody having the same CDRs as B100 with existing antibodies such as trastuzumab. As noted in the rejection, Fischer expressly teaches the need for development of alternative therapies to use in combination with existing therapies including trastuzumab (e.g., Fischer at page 3). Furthermore, the instantly claimed pharmaceutical composition or kit as amended require that the combination therapy comprises two antibodies that bind to different epitopes, but not expressly that the epitope is on a different subdomain of HER2. The instantly claimed method does not recite the limitation that the “second HER2 inhibitor” is an antibody or that it binds to a different epitope than the monoclonal antibody recited in the claims. Because Fischer and Lee teach that B100 and hz1E11 bind to different epitopes of HER2 than trastuzumab, this limitation is satisfied by the cited references.
Regarding Applicant's assertion that “there was no knowledge in the art that combining any two antibodies that bind different epitopes would be beneficial”, this argument is not found convincing for several reasons. First, the reference that appears to be cited in the disclosure as supporting this position, Scheuer (Cancer Research (2009) 69(24): 9930-9336), expressly teaches that the combination of trastuzumab and pertuzumab has a strongly enhanced antitumor effect and induces tumor regression in breast cancer and NSCLC xenograft models relative to either treatment as a monotherapy (e.g., Abstract; Results; Figures 1-3; Table 1). Scheuer expressly acknowledges that trastuzumab and pertuzumab bind to different epitopes of HER2 (e.g., Abstract; Introduction). Furthermore, Lee (at Figures 2A-2B) illustrates that the combination of trastuzumab and pertuzumab had a more potent inhibitory effect on NCI-N87 and BT-474 cell killing than either therapy alone. Regarding ADCC, which is an Fc-mediated effect, Scheuer teaches that each of trastuzumab and pertuzumab alone mediate a strong Fc-mediated ADCC activation effect and that “the simultaneous binding of trastuzumab and pertuzumab onto target cells mediates an additive but not synergistic effect on ADCC” (Discussion).
Applicant further argues that the combination of an antibody with the CDRs of B100 with trastuzumab or pertuzumab, which bind to different subdomains of HER2, display surprisingly synergistic effects and that “The Office Action Notes that Figures 2-3 show a synergistic effect of the combination of MAB270 and trastuzumab”. Remarks at page 11. Applicant submits that because antibody B100 and MAB270 differ by only a single CDR and bind similar epitopes on HER2, this difference “has no significant impact on efficacy” and that the results demonstrated for MAB270 would also be expected for B100 “as the two antibodies are highly similar”. Remarks at page 11. Applicant further submits that the combination of MAB270 with pertuzumab would be expected to be similar to that of MAB270 with trastuzumab because “Pertuzumab and trastuzumab are highly similar HER2 antibodies with well established similar effects” despite binding different epitopes. Remarks at page 11.
In response, as an initial matter, the following is an excerpt of what was expressly stated in the previous Office Action mailed in March 2026 (page 8):
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The previous Office further noted that the scope of the presently claimed invention is not congruent with any apparent synergistic effect illustrated by Applicant, and this position is maintained. Applicant's position that the B100 and MAB270 would be “expected” to have a similar effect on efficacy is not found convincing because the state of the art recognizes that the binding of an antibody to antigen is unpredictable and that even a single amino acid modification in the CDRs can have a significant impact on antigen binding (and subsequently, other therapeutic properties). See state of the prior art in the 35 U.S.C. § 112(a) written description rejection above. MPEP § 2163 (II)(A)(3)(a)(ii) states in relevant part: “("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). Secondly, it is disputed that pertuzumab and trastuzumab would be considered “similar” HER2 antibodies by those skilled in the art as contended by Applicant. First, as acknowledged by Applicant, the antibodies bind to different epitopes on separate subdomains of HER2. Secondly, these antibodies have distinct antigen-binding domain sequences as illustrated by Harding (US 2011/0177095 A1; supra) and Gennaro (US 2014/0308277 A1; supra). Scheuer (Cancer Research (2009) 69(24): 9930-9336; supra) further teaches that trastuzumab inhibits HER2-mediated proliferation by distinct mechanisms from pertuzumab, which is a HER2 dimerization inhibitor (e.g., Introduction). The instantly claimed pharmaceutical composition or kit is broadly drawn to the combination of an antibody having the same combination of heavy chain and light chain CDRs as B100 or MAB270 with “a second HER2 inhibitor”, provided that said second HER2 inhibitor is any anti-HER2 antibody that binds to “a different epitope” than the first antibody. Under the broadest reasonable interpretation of the claims, the different epitope could be immediately adjacent to that of B100 or MAB270 and on the same subdomain of HER2 ECD as that bound by B100 or MAB370. The instantly claimed method does not even require that the “second HER2 inhibitor” is an antibody, let alone an antibody binding a different epitope than the monoclonal antibody recited in the claim. Ultimately, as set forth in MPEP § 716.02(d), whether unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." The instant claims as presented do not meet this burden.
For at least these reasons, the rejection is maintained.
(2)
Claims 1, 8, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Fischer (WO 2017/191327 A2; supra) in view of Lee (EP 2998319 A1; supra) as applied to claims 1, 3-6, 8, 13-16, and 18-19 above, and further in view of Voutsas (International Journal of Radiation Biology (2013) 89(5): 319-325; cited in PTO-892).
The teachings of Fischer are recited in the 35 U.S.C. § 103 rejection above.
However, Fischer does not recite a pharmaceutical composition comprising antibody B100 further in combination with a second HER2 inhibitor (e.g., trastuzumab), further in combination with ionizing radiation.
The teachings of Lee are recited in the 35 U.S.C. § 103 rejection above.
Voutsas teaches that a single dose of 5 Gy gamma-irradiation induces HER2 overexpression in the human breast cancer cell lines (MDA-MB-321 and MDA-MB-435) having low basal levels of HER2 (e.g., Abstract; page 321, Results; Figures 1-2). Voutsas further illustrates that trastuzumab exerts greater antiproliferative effects on irradiated MDA-MB-231 and MDA-MD-435 breast cancer cells lines than one non-irradiated cell lines (e.g., page 321, Results; Figure 4). Voutsas concludes that irradiation-induced expression of HER2 in these cell lines renders them more susceptible to the antiproliferative effects of trastuzumab (e.g., Abstract; page 321, Results).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to possess a pharmaceutical composition comprising the combination of trastuzumab and a second anti-HER2 antibody, e.g., the B100 antibody taught by Fischer, further in combination with ionizing radiation (e.g., gamma-irradiation), based on the collective teachings of Fischer, Lee, and Voutsas. The skilled artisan would have been motivated to do so because, as taught by Lee, many patients with HER2-positive cancer do not respond to trastuzumab monotherapy, and a combinatorial treatment comprising two anti-HER2 antibodies that each bind a separate epitope of HER2 is more effective than either antibody alone. The skilled artisan would have been motivated to further add ionizing radiation (e.g., gamma-irradiation) because, as taught by Voutsas, gamma-irradiation induces HER2 expression in breast cancer cell lines with low basal expression of HER2 and increases their sensitivity to treatment with trastuzumab. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-HER2 antibodies taught by Fischer (B100) and Lee (hz1E11) are functional equivalents in that both possess the same qualities of (1) binding specifically to HER2 at a different epitope than trastuzumab, and (2) potently inducing apoptosis of cancer cells, and it would thus have been obvious to try substituting hz1E11 with B100 in a HER2 combination therapy. In addition, one of ordinary skill in the art would have recognized the suitability of further adding gamma-irradiation for the purpose of further enhancing the therapeutic effect of trastuzumab in a HER2-positive cancer which might otherwise be less sensitive to treatment.
Response to Arguments
Applicant's arguments filed August 13, 2026 have been fully considered but they are not persuasive.
Applicant asserts that, as previously discussed for the rejection of Fisher in view of Lee, “neither Fischer nor Lee teach or suggest a combination of HER2 antibodies that bind different epitopes” on HER2. Applicant submits that Voutsas does not remedy these deficiencies since Voutsas does not disclose a combination of anti-HER2 antibodies, let alone two anti-HER2 antibodies that bind to different epitopes. Remarks at page 12.
In response, regarding Applicant's arguments with respect to Fischer and Lee, reference is made to the Response above. In response to Applicant's arguments with respect to alleged deficiencies of Voutsas, it is noted that the teaching of a combination treatment comprising two anti-HER2 antibodies that bind to separate epitopes of HER2 is already provided by Fischer and Lee. Voutsas is cited for its teachings with respect to the combination of an anti-HER2 antibody (e.g., trastuzumab) with gamma-irradiation for treatment of a HER2-expressing cancer, since gamma-irradiation increases susceptibility of the cancer cells to the anti-HER2 antibody trastuzumab.
Accordingly, the rejection is maintained.
Double Patenting (Maintained)
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
(1)
Claims 1, 3-6, 13-16, and 18-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7-8, 12, 15, and 17-19 of U.S. Patent No. 11,091,561 in view of Lee (EP 2998319 A1; supra).
The ‘561 patent claims a monoclonal antibody that specifically binds to HER2, or a fragment or derivative thereof that binds to HER2, denoted “B100”, which comprises a VH comprising the amino acid sequence of SEQ ID NO: 4 (which shares 100% identity to instant SEQ ID NO: 80 and comprises corresponding CDRs comprising the amino acid sequences of instant SEQ ID NO: 1-3, respectively) and a VL comprising an amino acid sequence of SEQ ID NO: 10 (which shares 100% identity to SEQ ID NO: 89 and comprises corresponding CDRs comprising the amino acid sequences of instant SEQ ID NO: 4-6, respectively), wherein the antibody is a humanized antibody (patented claims 1-4, 7-8, and 15), relevant to the antibody recited in claims 1 and 3-5. Relevant to claim 6, the antibody does not compete with trastuzumab in an epitope competition assay (patented claim 12). Patented claim 18 recites a pharmaceutical composition comprising a therapeutically effective amount of the B100 antibody of patented claim 1.
Relevant to claim 13, the ‘561 patent claims a method of treating a HER2-mediated disease that comprises administering to a subject in need thereof an antibody according to patent claim 1 or a pharmaceutical composition comprising the same to treat the HER2-mediated disease (patented claims 17 and 19).
However, the ‘561 patent does not teach a pharmaceutical composition comprising antibody B100 further in combination with a second HER2 inhibitor (e.g., trastuzumab), nor a method of treating a HER2-positive cancer by administering such a combination of anti-HER2 agents.
The teachings of Lee with respect to combination therapies for HER2-positive cancers, comprising trastuzumab in combination with a second anti-HER2 antibody, are recited in the 35 U.S.C. § 103 rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to make and use a pharmaceutical composition comprising the combination of trastuzumab and a second anti-HER2 antibody, e.g., the B100 antibody taught in the ‘561 patent, in a method of treating a HER2-positive cancer, based on the collective teachings of the ‘561 patent and Lee. The skilled artisan would have been motivated to do so because, as taught by Lee, many patients with HER2-positive cancer do not respond to trastuzumab monotherapy, and a combinatorial treatment comprising two anti-HER2 antibodies that each bind a separate epitope of HER2 is more effective than either antibody alone. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-HER2 antibodies taught by the ‘561 patent (B100) and Lee (hz1E11) are functional equivalents in that both bind specifically to HER2 at a different epitope than trastuzumab. Accordingly, it would have been obvious to try substituting hz1E11 with B100 in a HER2 combination therapy.
(2)
Claims 1, 8, and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7-8, 12, 15, and 17-19 of U.S. Patent No. 11,091,561 in view of Lee (EP 2998319 A1; supra) as applied to claims 1, 3-6, 13-16, and 18-19 above, and further in view of Voutsas (International Journal of Radiation Biology (2013) 89(5): 319-325; supra).
The teachings of the ‘561 patent are recited in the non-statutory double patenting rejection above.
However, the ‘561 patent does not recite a pharmaceutical composition comprising antibody B100 in combination with a second HER2 inhibitor (e.g., trastuzumab), further in combination with ionizing radiation.
The teachings of Lee and Voutsas are recited in the 35 U.S.C. § 103 rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to possess a pharmaceutical composition comprising the combination of trastuzumab and a second anti-HER2 antibody, e.g., the B100 antibody taught in the ‘561 patent, further in combination with ionizing radiation (e.g., gamma-irradiation), based on the collective teachings of the ‘561 patent, Lee, and Voutsas. The skilled artisan would have been motivated to do so because, as taught by Lee, many patients with HER2-positive cancer do not respond to trastuzumab monotherapy, and a combinatorial treatment comprising two anti-HER2 antibodies that each bind a separate epitope of HER2 is more effective than either antibody alone. The skilled artisan would have been motivated to further add ionizing radiation (e.g., gamma-irradiation) because, as taught by Voutsas, gamma-irradiation induces HER2 expression in breast cancer cell lines with low basal expression of HER2 and increases their sensitivity to treatment with trastuzumab. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-HER2 antibodies taught in the ‘561 patent (B100) and Lee (hz1E11) are functional equivalents in that both bind specifically to HER2 at a different epitope than trastuzumab, and it would thus have been obvious to try substituting hz1E11 with B100 in a HER2 combination therapy. In addition, one of ordinary skill in the art would have recognized the suitability of further adding gamma-irradiation for the purpose of further enhancing the therapeutic effect of trastuzumab in a HER2-positive cancer which might otherwise be less sensitive to treatment.
(3)
Claims 1, 3-6, 13-16, and 18-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 10-11, and 14-16 of U.S. Patent No. 12,129,307 in view of Lee (EP 2998319 A1; supra).
The ‘307 patent claims 1 and 15 recite a fragment of derivative of the monoclonal antibody B100, which comprises a VH comprising the amino acid sequence of SEQ ID NO: 4 (which shares 100% identity to instant SEQ ID NO: 80 and comprises corresponding CDRs comprising the amino acid sequences of instant SEQ ID NO: 1-3, respectively) and a VL comprising an amino acid sequence of SEQ ID NO: 10 (which shares 100% identity to SEQ ID NO: 89 and comprises corresponding CDRs comprising the amino acid sequences of instant SEQ ID NO: 4-6, respectively), wherein the antibody fragment binds to a different epitope than trastuzumab (patented claims 8 and 10-11), relevant to claims 1 and 3-4. Patented claim 16 recites that the fragment is a humanized antibody fragment, relevant to instant claim 5. Patented claim 14 recites a pharmaceutical composition comprising the antibody fragment.
However, the ‘307 patent does not teach a pharmaceutical composition comprising antibody B100 further in combination with a second HER2 inhibitor (e.g., trastuzumab), nor a method of treating a HER2-positive cancer by administering such a combination of anti-HER2 agents.
The teachings of Lee with respect to combination therapies for HER2-positive cancers, comprising trastuzumab in combination with a second anti-HER2 antibody, are recited in the 35 U.S.C. § 103 rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to make and use a pharmaceutical composition comprising the combination of trastuzumab and a second anti-HER2 antibody, e.g., the B100 antibody taught in the ‘307 patent, in a method of treating a HER2-positive cancer, based on the collective teachings of the ‘307 patent and Lee. The skilled artisan would have been motivated to do so because, as taught by Lee, many patients with HER2-positive cancer do not respond to trastuzumab monotherapy, and a combinatorial treatment comprising two anti-HER2 antibodies that each bind a separate epitope of HER2 is more effective than either antibody alone. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-HER2 antibodies taught by the ‘307 patent (B100) and Lee (hz1E11) are functional equivalents in that both bind specifically to HER2 at a different epitope than trastuzumab. Accordingly, it would have been obvious to try substituting hz1E11 with B100 in a HER2 combination therapy.
(4)
Claims 1, 8, and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 10-11, and 14-16 of U.S. Patent No. 12,129,307 in view of Lee (EP 2998319 A1; supra) as applied to claims 1, 3-6, 13-16, and 18-19 above, and further in view of Voutsas (International Journal of Radiation Biology (2013) 89(5): 319-325; supra).
The teachings of the ‘307 patent are recited in the non-statutory double patenting rejection above.
However, the ‘307 patent does not recite a pharmaceutical composition comprising antibody fragment B100 in combination with a second HER2 inhibitor (e.g., trastuzumab), further in combination with ionizing radiation.
The teachings of Lee and Voutsas are recited in the 35 U.S.C. § 103 rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to possess a pharmaceutical composition comprising the combination of trastuzumab and a second anti-HER2 antibody, e.g., the B100 antibody fragment taught in the ‘307 patent, further in combination with ionizing radiation (e.g., gamma-irradiation), based on the collective teachings of the ‘307 patent, Lee, and Voutsas. The skilled artisan would have been motivated to do so because, as taught by Lee, many patients with HER2-positive cancer do not respond to trastuzumab monotherapy, and a combinatorial treatment comprising two anti-HER2 antibodies that each bind a separate epitope of HER2 is more effective than either antibody alone. The skilled artisan would have been motivated to further add ionizing radiation (e.g., gamma-irradiation) because, as taught by Voutsas, gamma-irradiation induces HER2 expression in breast cancer cell lines with low basal expression of HER2 and increases their sensitivity to treatment with trastuzumab. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-HER2 antibodies taught in the ‘307 patent (B100) and Lee (hz1E11) are functional equivalents in that both bind specifically to HER2 at a different epitope than trastuzumab, and it would thus have been obvious to try substituting hz1E11 with B100 in a HER2 combination therapy. In addition, one of ordinary skill in the art would have recognized the suitability of further adding gamma-irradiation for the purpose of further enhancing the therapeutic effect of trastuzumab in a HER2-positive cancer which might otherwise be less sensitive to treatment.
Response to Arguments (Combined)
Applicant's arguments filed August 13, 2026 have been fully considered but they are not persuasive.
Applicant acknowledges each of the rejections above and notes that “appropriate corrective action of filing a terminal disclaimer or distinguishing the claims once allowable subject matter is obtained” (Remarks at pages 12-13).
In response, Applicant’s request to hold the nonstatutory double patenting rejections in abeyance is denied. The rejections will remain in place until they are overcome by amendment, terminal disclaimer, or otherwise.
Conclusion
No claims are allowed.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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