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 .
DETAILED ACTION
Restriction/Election
1. Applicant’s election without traverse of the species lung cancer and lung cancer cells is acknowledged in the reply filed on 05/26/2026.
2. Claims 1-11, 13-18, and 21-24 are pending. Claims 1-11, 13-18, and 21-23 are currently under consideration. Claim 24 is withdrawn from consideration as being drawn to a non-elected species.
Information Disclosure Statement
3. The information disclosure statement filed on 01/12/2024 has been considered by the Examiner and an initialed copy of the form PTO-1449 is attached to this communication.
Drawings
4. The drawings filed on 01/12/2024 are accepted by the examiner.
Claim Rejections[Symbol font/0xBE]35 USC § 112 (a)
5. The following is a quotation of the first paragraph of 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.
6. Claims 1-11, 13-18, and 21-22 are rejected under 35 U.S.C. 112(a), 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 at the time the application was filed, had possession of the claimed invention.
To satisfy the written description requirement, a patent 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. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
Claim 1 is drawn to a method of treating an individual that has an ErbB-2 and ErbB-3 positive cell comprising administering to the individual a bispecific antibody that comprises a first antigen-binding site that can bind an extracellular part of ErbB-2, and a second antigen-binding site that can bind an extracellular part of ErbB-3, wherein the cell comprises an NRG1 fusion gene comprising at least a portion of the NRG1-gene fused to a sequence from a different chromosomal location. Claim 7 is drawn to a method of treating an individual that has an ErbB-2 and ErbB-3 positive tumor, wherein cells of tumor express an NRG1 fusion gene comprising at least the 3’ end of the NRG1-gene fused to a 5’ sequence from a different chromosomal location, the method comprising administering to the individual a bispecific antibody that comprises a first antigen-binding site that can bind an extracellular part of ErbB-2, and a second antigen-binding site that can bind an extracellular part of ErbB-3. Claims 2-6, 8-18, and 21 depend from claims 1 or 7. Claim 22 recites a partial structure for the bispecific antibody. The claims do not require that the bispecific antibody possess any particularly conserved structure nor other disclosed distinguishing feature. Thus, the claims recite a genus of bispecific antibodies without any defined structure.
For each claim drawn to a genus, MPEP §2163 II.A.3(a) ii) (page 2100-189) states, “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 (see i)(A), above), reduction to drawings (see i)(B), above), or 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 (see i)(C), above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406”. In the instant case, the specification discloses one bispecific antibody, MCLA-28 (or PB4188) (Examples), even though it provides a long list of putative bispecific antibodies (see, e.g., pages 38-54 of the specification). Such a limited disclosure is insufficient to support the broad genus of bispecific antibodies.
The prior art teaches a bispecific antibody, MM-111, which targets ERBB2 and ERBB3 (Mol. Cancer Ther. 11 (3): 582–593, 2012). The prior art also teaches CD74–NRG1 gene fusion (Fernandez-Cuesta et al, Clin Cancer Res 21 (9): 1989–1994, 2015; US Patent No. 10,208,354 B2) and SLC3A2-NRG1 fusion in invasive mucinous adenocarcinoma of the lung (Shin et al., Oncotarget. 2016 Oct 25; 7(43): 69450–69465). The DOC4-NRG1 gene fusion is known to be present in MDA-MB-175 primary breast cancer cell line as acknowledged in the specification (page 65, the 2nd paragraph). However, the prior art does not provide compensatory structural or correlative teachings sufficient to enable one of skill to identify what other bispecific antibodies might be. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the genus of bispecific antibodies and thus the instantly claimed method using the same.
7. Claims 1-11, 13-18, and 21-23 are rejected under 35 U.S.C. 112(a), because the specification, while being enabling for a method of treating a human patient with advanced/metastatic non-small cell lung cancer with invasive mucinous adenocarcinoma and an NRG1 fusion, comprising administering the patient a therapeutically effective amount of a bispecific antibody, MCLA-128, wherein the cancer cell overexpresses ErbB-2 and ErbB-3, wherein the NRG1 fusion is selected from the group consisting of CD74-NRG1, VAMP2–NRG1, SLC3A2-NRG1, RBPMS-NRG1, WRN-NRG1, and SDC4-NRG1, and WRN-NRG1, does not reasonably provide enablement for the instantly claimed method. 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.
The factors that are considered when determining whether a disclosure satisfies enablement requirement include: (i) the quantity of experimentation necessary; (ii) the amount of direction or guidance presented; (iii) the existence of working examples; (iv) the nature of the invention; (v) the state of the prior art; (vi) the relative skill of those in the art; (vii) the predictability or unpredictability of the art; and (viii) the breadth of the claims. Ex Parte Forman, 230 USPQ 546 (Bd Pat. App. & Int. 1986); In re Wands, 858 F. 2d 731, 8 USPQ 2d 1400 (Fed. Cir. 1988).
Claims 1-6, 9-11, 13-18, and 21-23 are drawn to a method of treating an individual that has an ErbB-2 and ErbB-3 positive cell comprising administering to the individual a bispecific antibody that comprises a first antigen-binding site that can bind an extracellular part of ErbB-2, and a second antigen-binding site that can bind an extracellular part of ErbB-3, wherein the cell comprises an NRG1 fusion gene comprising at least a portion of the NRG1-gene fused to a sequence from a different chromosomal location. Claims 7-8 are drawn to a method of treating an individual that has an ErbB-2 and ErbB-3 positive tumor, wherein cells of tumor express an NRG1 fusion gene comprising at least the 3’ end of the NRG1-gene fused to a 5’ sequence from a different chromosomal location, the method comprising administering to the individual a bispecific antibody that comprises a first antigen-binding site that can bind an extracellular part of ErbB-2, and a second antigen-binding site that can bind an extracellular part of ErbB-3. The claims are broad because they encompass a method of treating an individual that has any types of ErbB-2 and ErbB-3 positive cell or any types of ErbB-2 and ErbB-3 positive tumors comprising administering any bispecific antibodies to a subject that comprises a first antigen-binding site that can bind an extracellular part of ErbB-2, and a second antigen-binding site that can bind an extracellular part of ErbB-3.
The specification does not provide sufficient guidance/direction or working examples on how to make and use the instantly claimed invention. The specification discloses that a HER2xHER3 bispecific antibody, PB4188, effectively accumulated in tumors as compared to the HER3 monoclonal antibody (Example 1). The bispecific antibody MCLA-128 (also referred as PB4188) fully inhibited HRG-induced HER2:HER3 dimerization with the highest potency (Example 2; Table 1). In a human ovarian cancer PDX model of OV-10-0050 in BALB/c nude mice, treatment with MCLA-128 at 25 mg/kg (QWx5 weeks) produced significant antitumor activity (Example 3; Tables 3-4, Figure 4). In Example 4, MCLA-128 shows an anti-tumor activity in MDA-MB-175 breast cancer cell line in vitro and in OV-10-0050 in vivo (Example 4, Figure 7). Example 5 discloses a phase I/II study of MCLA-128, a full length IgG1 bispecific antibody targeting HER2 and HER3, in patients with advanced/metastatic non-small cell lung cancer with invasive mucinous adenocarcinoma or documented NRG1 fusion.
The specification discloses one bispecific antibody, MCLA-28 (or PB4188), even though it provides a long list of putative bispecific antibodies (see, e.g., pages 38-54 of the specification). The specification disclosed
The prior art teaches CD74–NRG1 gene fusion (Fernandez-Cuesta et al, Clin Cancer Res 21 (9): 1989–1994, 2015; US Patent No. 10,208,354 B2) and SLC3A2-NRG1 fusion in invasive mucinous adenocarcinoma of the lung, a subpopulation of non-small cell lung cancer (Shin et al., Oncotarget. 2016 Oct 25; 7(43): 69450–69465). Fernandez-Cuesta et al teach that blocking the activity of these receptors may be the best strategy to treat NRG1-rearranged tumors (page 1991, right column, the 2nd paragraph; page 1992, top of the right column), one inhibitor is MM-III, a bispecific antibody, which targets ERBB2 and ERBB3 (Table 1). Other NRG1 gene fusions, VAMP2-NRG1, RPBMS-NEG1 and WRN-NRG1 in lung cancer and RAB2IL1-NRG1 in ovarian cancer are also known in the art. On the other hand, while the DOC4-NRG1 gene fusion has been detected in MDA-MB-175 primary breast cancer cell line, the relevance of DOC4-NRG1 gene fusion in breast cancer patients has been debated in the field. Sa´nchez-Valdivieso et al teach that NRG-1 (γ-Heregulin) has no biological significance in primary breast cancer (Br J Cancer 86(8): 1362–1363, 2002). Howarth et al teach that the fusion in MDA-MB-175 is the result of a very complex genomic rearrangement and that NRG1 can be pro-apoptotic and is inactivated in some breast cancers (Breast Cancer Res. 23(1):3, Jan. 7, 2021, in particular Abstract, Results). Howarth et al further teach the complexity of rearrangements of NRG1 in breast cancers and confirm that some do not activate but inactivate. Careful interpretation of NRG1 rearrangements will therefore be necessary for appropriate patient management (see, e.g., Abstract, conclusion). Thus, it is unpredictable whether an NRG1 gene fusion has biological significance in a given primary breast cancer.
The courts have stated that patent protection is granted in return for an enabling disclosure. Reasonable detail must be provided in order to enable members of the public to understand and carry out the invention. See Genetech v. Novo Nordick A/S (CAFC) 42 USPQ2d 1001 (1997). Similarly, as stated in Rasmusson v SmithKline Beecham Corp., 75 USPQ2d 1297-1303 (CAFC 2005), “if mere plausibility were the test for enablement under section 112, Applicants could obtain patent rights to ‘inventions’ consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the 'inventor’ would be rewarded the spoils instead of the party who demonstrated that the method actually worked. The scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis. In the instant case, the evidence on the record supports that the specification does not enable the claimed invention commensurate in scope with these claims.
Due to the large quantity for experimentation necessary to use the broad method, the limited directions guidance presented in the specification regarding the same, the limited working example directed to the same, the complex nature of the invention, the unpredictability in the art, and the breadth of the claims, undue experimentation would be required for the skilled artisan to make and use the claimed invention commensurate in scope with these claims.
Claim Rejections[Symbol font/0xBE]35 USC § 112 (b)
8. The following is a quotation of the second paragraph of 35 U.S.C. 112:
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.
9. Claim 1-11, 13-18, and 21-23 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 is drawn to a method of treating an individual that has an ErbB-2 and ErbB-3 positive cell comprising administering to the individual a bispecific antibody that comprises a first antigen-binding site that can bind an extracellular part of ErbB-2, and a second antigen-binding site that can bind an extracellular part of ErbB-3, wherein the cell comprises an NRG1 fusion gene comprising at least a portion of the NRG1-gene fused to a sequence from a different chromosomal location. The claim is indefinite because it does not indicate what diseases are treated. Claims 1-6, 9-11, 13-18, and 21-23 are rejected as dependent claims from claim 1, either directly or indirectly. Likewise, claim 7 is drawn to a method of treating an individual that has an ErbB-2 and ErbB-3 positive tumor. The claim is vague and unclear because it does not clearly indicate that what diseases are treated. Claim 8 is rejected as a dependent claim from claim 7.
Claim 1 is indefinite because it recites “a dose of 750 mg”, which does not indicate what the dose is based upon and the frequency of administration.
Claim Rejections under 35 USC § 103(a)
10. The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
11. Claims 1-11, 13, and 18 are rejected under 35 U.S.C. 103(a) as being unpatentable over Fernandez-Cuesta et al (Clin Cancer Res 21 (9): 1989–1994, 2015) or US Patent No. 10,208,354 B2. The rejection below is set forth based on the non-patent publication.
Fernandez-Cuesta et al teach a recurrent CD74–NRG1 gene fusions, which result in the expression of the NRG1 III-β3 isoform in the otherwise NRG1-negative invasive mucinous subtype of lung adenocarcinomas (page 1991, left column, the 2nd paragraph). The NRG-fusion gene expresses a protein that comprises an NRG1 EGF-like domain (see, e.g., Abstract; Figure 1). Fernandez-Cuesta et al teach that NRG1 fusions act through activation of ERBB2–ERBB3 heterodimers and that blocking the activity of these receptors may be the best strategy to treat NRG1-rearranged tumors (page 1991, right column, the 2nd paragraph; page 1992, top of the right column), one inhibitor is MM-III, a bispecific antibody, which targets ERBB2 and ERBB3 (Table 1).
Fernandez-Cuesta et al do not explicitly teach the dose of 750 mg recited in claim 1.
However, it would have been obvious for one skilled in the art to determine the dose of the bispecific antibody to be administered with a reasonable expectation of success. One would have been motivated to do so because determining the optimal dose is well-known in the art and routinely practiced by an artisan.
12. Claims 14-17 are rejected under 35 U.S.C. 103(a) as being unpatentable over Fernandez-Cuesta et al (Clin Cancer Res 21 (9): 1989–1994, 2015) or US Patent No. 10,208,354 B2 as applied to claims 1-11, 13, and 18 above, and further in view of McDonagh et al (Mol. Cancer Ther. 11 (3): 582–593, 2012).
Fernandez-Cuesta et al teach a method of treating a subject that has an ErbB-2 and ErbB-3 positive tumor as applied to claims 1-3, 6-13, and 18 above.
Fernandez-Cuesta et al do not explicitly teach the limitations recited in claims 14-17.
McDonagh et al teach a bispecific antibody, MM-111, which targets ERBB2 and ERBB3. McDonagh et al teach detection of f ErbB1, ErbB2, and ErbB3 receptors per cell (Table 1). McDonagh et al teach that a bispecific antibody approach is optimal for inhibiting ErbB3 in ErbB2-overexpressing cells (page 585).
It would have been obvious for one skilled in the art to detect the cell surface receptor density of ErbB-1, ErbB-2, ErbB-3, or ErbB-4 as taught by McDonagh et al, to treat an individual who has undergone a therapy targeted towards EGFR inhibition, or to administering to an individual an Erb-1 inhibitor, such as cetuximab, with a reasonable expectation of success. One would have been motivated to do so because (i). ERBB1 (EGFR), ERBB2 (HER2), ERBB3, and ERBB4 constitute the ERBB family of transmembrane receptor tyrosine kinases, which, upon ligand binding, induce the phosphorylation of their intrinsic kinase domain, resulting in the activation of the downstream PI3K–AKT and MAPK pathways as taught by Fernandez-Cuesta et al (page 1989, left column); and a bispecific antibody approach is optimal for inhibiting ErbB3 in ErbB2-overexpressing cells as taught by McDonagh et al above; (ii). Cetuximab is a well-known anticancer drug that targets EGFR; and (iii). a dual inhibitor of ErbB-2/ErbB-3 provides an alternative therapy for an individual who has undergone a therapy targeted toward EGFR inhibition.
Conclusion
13. No claims are allowed.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Ruixiang Li whose telephone number is (571) 272-0875. The examiner can normally be reached on Monday through Friday from 8:30 am to 5:00 pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa Ford, can be reached on (571) 272-0857. The fax number for the organization where this application or proceeding is assigned is (571) 273-8300.
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/RUIXIANG LI/ Examiner, Art Unit 1674
June 3, 2026
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