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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 June 26, 2026 has been entered.
Application Status
The amended claims filed June 26, 2026 are acknowledged. Claims 31 and 47 have been amended. Claims 31, 34, 37-41, 43-44, and 47-49 are pending and under examination herein.
WITHDRAWN CLAIM OBJECTIONS AND REJECTIONS
The objection to claim 31 is withdrawn in view of Applicant's amendments to the claim.
The rejection of claims 31, 34, 37-41, 43-44, and 47-49 under 35 U.S.C. § 112(b) are withdrawn in view of Applicant's amendments to claim 31.
The rejection of claims 31, 34, 37-41, 43-44, and 47-49 under 35 U.S.C. § 112(a) as failing to comply with the written description requirement are withdrawn in view of Applicant's amendments to claim 31.
NEW REJECTIONS NECESSITATED BY CLAIM AMENDMENT
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 31, 34, 37, 39-41, 43-44, and 47-48 are rejected under 35 U.S.C. 103 as being unpatentable over Throsby (US 2018/0312604 A1; cited in PTO-892) in view of Hendrikx (The Oncologist (2017) 22(10): 1212-1221; cited in PTO-892) and Tsurushita (WO 2020/102233 A1; international filing date: November 12, 2019).
Throsby discloses bispecific antibodies that bind to an extracellular part of EGFR and to an extracellular part of LGR5, e.g., PB10651, and methods of treating cancers such as stomach cancer, gastrointestinal cancer, or colorectal cancer, that comprise administering said bispecific antibody to a human subject (e.g., Abstract; claims 1-13; ¶ 0006-0039, 0059, 0063, 0089-0090, 0295-0299; Table 6, pages 57-58; Figures 10, 13), relevant to claims 31, 39, and 41. Relevant to claims 31 and 47, the PB10651 bispecific antibody comprises an anti-EGFR MF3755 VH comprising the amino acid sequence of SEQ ID NO: 20 (which shares 100% sequence identity to instant SEQ ID NO: 4), an anti-LGR5 MF5816 VH comprising the amino acid sequence of SEQ ID NO: 26 (which shares 100% sequence identity to instant SEQ ID NO: 13), and a common light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 80 (which shares 100% sequence identity to instant SEQ ID NO: 122) (e.g., ¶ 0067, 0415-0416, 0655; pages 89, 92, 120).
Relevant to claims 34 and 37, Throsby discloses that toxicity of PB10651 was assessed using weekly intravenous dosages of control (vehicle only), 2.5 mg/kg, 7.5 mg/kg, and 25 mg/kg in cynomolgus monkeys (e.g., Example 8, ¶ 0729-0731). Throsby discloses that even at the highest dose administered, neither skin toxicity nor gastrointestinal toxicity were observed after repeated administration of PB10651.
Relevant to claims 40 and 48, Throsby describes measuring expression of EGFR and LGFR5 in a patient-derived xenograft (PDX) model of esophageal cancer, ES02011, with anti-LGR5 and anti-EGFR antibodies (e.g., Example 1; Tables 9-10, page 58).
Relevant to claims 43-44, the ADCC activity of the bispecific antibody may be enhanced according to known methods in the art, e.g., afucosylation (e.g., ¶ 0059-0062, 0430, 0455; Figures 19, 33). Throsby teaches that efficacy of afucosylated PB10651 was assessed in immunocompromised mice bearing PDX colorectal cancer tumors having different mutations in the KRAS gene (e.g., Example 7, ¶ 0714-0719).
However, Throsby does not expressly teach administering PB10651 at a flat dose of 1500 mg regardless of body weight.
Hendrikx reviews the advantages of fixed dosing of monoclonal antibodies in the field of oncology. Hendrikx teaches that most monoclonal antibodies in oncology are administered in body-size-based dosing schedules (e.g., body surface area (BSA, in m2) or mg/kg), which are believed to correct for variability in both drug distribution and elimination among patients (e.g., Introduction, page 1212). Hendrikx argues that fixed dosing of monoclonal antibodies has several advantages including efficiency of compounding, reduced drug spillage, fewer medication errors, and decreased costs (e.g., Introduction, page 1213; page 1219). Hendrikx teaches that monoclonal antibodies are cleared in a linear fashion via proteolytic catabolism and intracellular degradation after target binding, the latter of which is likely not body weight-dependent (e.g., pages 1213 and 1215, text). Summarizing the results of in silico studies, Hendrikx notes that when minimal effects of body weight are observed on the volume of distribution and clearance of an antibody in plasma, fixed dose administration reduces interpatient variability compared to body weight-based dosing (e.g., pages 1215-1216). Even when strong effects of body weight are observed, Hendrikx argues that fixed dosing can still be considered for monoclonal antibodies with a wide therapeutic range for practical reasons (e.g., page 1217; Table 1). Citing the anti-EGFR antibody panitumumab as an example, Hendrikx notes that effects of body weight on antibody clearance and volume distribution were limited, which together with the wide therapeutic window of this drug suggests that a fixed dosing could successfully be employed (e.g., page 1219). Table 1 illustrates other monoclonal antibodies approved for treatment of cancer, some of which have approved therapeutic windows comprising a flat dose of 1500 mg (e.g., obinutuzumab, ofatumumab).
Tsurushita discloses bispecific antibodies that comprise a first binding site specific for EGFR and a second binding site (e.g., Abstract; claims 25-30; ¶ 00126-01142). Tsurushita teaches that bispecific antibodies of the invention may be intravenously administered for the treatment of cancers including any of those in which one arm of the bispecific antibody binds to a target that is (over)expressed in the cancer, at a fixed dosage of 1500 mg, depending on the condition of the patient and response to prior treatment (e.g., ¶ 0089-0098), i.e., the dosage can be optimized.
Taken together, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a method of treating a cancer such as that taught by Throsby wherein the method comprises administering a flat dose of 1500 mg of the anti-EGFR/anti-LGR5 bispecific antibody PB10651, through the process of routine optimization. The skilled artisan would have been motivated to use a flat dose because Hendrikx teaches that fixed dosage schedules are justified based on pharmacokinetics and furthermore have several advantages, including lower healthcare costs, drug spillage, and medication errors. In addition, Hendrikx notes that the pharmacokinetics of at least one anti-EGFR antibody known in the art (panitumumab) is amenable to a fixed dose regimen. There would have been a reasonable expectation of success because Throsby teaches that PB10651 is widely tolerated, with minimal skin or gastrointestinal toxicities, at a wide range of body weight-based dosages, and Tsurushita presents a showing that a bispecific EGFR-targeting antibody may be administered at a flat dosage of 1500 mg for the purpose of treating disease.
With further regard to the specific dosages recited in the instant claims, MPEP § 2144.05(II)(A) states, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal therapeutic doses, and one of ordinary skill in the art would have arrived at the dosage of 1500 mg PB10651 through the process of routine optimization.
(2)
Claims 31, 34, 37-39, 41, 43-44, and 48-49 are rejected under 35 U.S.C. 103 as being unpatentable over Throsby (US 2018/0312604 A1; supra) in view of Hendrikx (The Oncologist (2017) 22(10): 1212-1221; supra) and Tsurushita (WO 2020/102233 A1; supra) as applied to claims 31, 34, 37, 39-41, 43-44, and 47-48 above, further in view of Wang (Cancer (2007) 109(4): 658-667) and Goletz (US 2016/0068609 A1; cited in IDS).
The teachings of Throsby are recited in the 35 U.S.C. § 103 rejection above.
However, Throsby does not expressly teach a method of cancer treatment wherein the cancer is a gastro-esophageal junction cancer.
The teachings of Hendrikx are recited in the 35 U.S.C. § 103 rejection above.
Wang investigated the expression of EGFR in esophageal and esophagogastric junction (EGJ) adenocarcinomas. Wang teaches that EGFR expression in patient-derived tumor specimens from esophageal and EGJ adenocarcinomas was correlated with poorer prognostic outcomes, including higher pathologic tumor classification and lymph node metastases as well as shorter disease-free survival and overall survival (e.g., Abstract; Tables 1 and 2).
Goletz describes anti-EGFR antibodies with reduced fucosylation, which demonstrate anti-tumor efficacy and improved adverse side effect profiles (e.g., Abstract). Goletz teaches that the anti-EGFR antibodies of the invention can be used to treat gastroesophageal junction cancer, gastric cancer, esophageal cancer, and others (e.g., ¶ 0063, 0145, 0171). Goletz teaches that pharmaceutical compositions comprising the anti-EGFR antibodies of the invention are administered intravenously, in intervals of every week or every second week (e.g., ¶ 0211-0215), pertinent to claims 34 and 37-38. When the antibody is administered in intervals of two weeks the dose may be in the range of from 1100 mg to 1700 mg (e.g., ¶ 0215). Goletz further teaches that afucosylation of IgG1 antibodies enhances ADCC (e.g., ¶ 0007, 0385-0387), further relevant to claims 43-44.
Based on these teachings, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out the treatment method collectively taught by Throsby and Hendrikx in a human subject with gastroesophageal junction cancer. The skilled artisan would have been motivated to do so because Wang teaches that EGFR expression is associated with worse prognostic outcomes in patients with esophageal and EGJ adenocarcinomas. There would have been a reasonable expectation of success because Goletz provides a proof-of-concept that an EGFR-targeting antibody can be administered for treatment of a cancer of the gastroesophageal junction.
Double Patenting
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 31, 34, 37, 43, and 47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11,939,394 (cited in PTO-892) in view of Roovers (Abstract #32 in: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl): Abstract nr 32. doi:10.1158/1538-7445.AM2017-32; cited in IDS), Hendrikx (The Oncologist (2017) 22(10): 1212-1221; supra), and Tsurushita (WO 2020/102233 A1; supra).
The ‘394 reference patent claims a bispecific antibody that comprises a variable domain that binds an extracellular part of EGFR and a variable domain that binds an extracellular part of LGR5, wherein the anti-EGFR VH chain comprises the amino acid sequence of SEQ ID NO: 20 (which shares 100% sequence identity to instant SEQ ID NO: 4), the anti-LGR5 VH chain comprises the amino acid sequence of SEQ ID NO: 26 (which shares 100% sequence identity to instant SEQ ID NO: 13) (patented claims 1, 12, 24), and a VL comprising the amino acid sequence of SEQ ID NO: 80 (which shares 100% sequence identity to instant SEQ ID NO: 122), relevant to claims 31 and 47. The ‘394 reference patent also claims a pharmaceutical composition comprising an antibody comprising the CDRs of said bispecific antibody.
However, the ‘394 reference patent does not expressly teach a method of treating cancer that comprises administering a flat dose of 1500 mg of said bispecific antibody.
Roovers discloses the preclinical evaluation of MCLA-158, an ADCC-enhanced bispecific antibody that binds to an extracellular part of EGFR (domain III) and to an extracellular part of LGR5 (N-Cap/1st LRR). Relevant to claims 31, 34, 37, and 43, Roovers describes once-weekly intravenous administration of MCLA-158 for four weeks to cynomolgus monkeys bearing patient-derived colorectal cancer xenografts. Roovers reports that MCLA-158 demonstrated inhibitory activity in 74% of tumor organoids independent of KRAS mutations status. Roovers also notes that initial evaluations of toxicity in cynomolgus monkeys after repeated dosing at 25 mg/kg did not demonstrate any pathological findings. Roovers concludes that these preclinical data suggest MCLA-158 could benefit patients with metastatic colorectal cancer.
The teachings of Hendrikx and Tsurushita 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 administer the bispecific antibody taught in the reference patent in a method of treating colorectal cancer such as that collectively taught by Roovers and Hendrikx, at a flat dosage of 1500 mg as determined through the process of routine optimization. The skilled artisan would have been motivated to use a flat dose because Hendrikx teaches that fixed dosage schedules are justified based on pharmacokinetics and furthermore have several advantages, including lower healthcare costs, drug spillage, and medication errors. In addition, Hendrikx notes that the pharmacokinetics of at least one anti-EGFR antibody known in the art (panitumumab) is amenable to a fixed dose regimen. There would have been a reasonable expectation of success because those of ordinary skill in the art would recognize that the bispecific antibodies recited in the reference patent and by Roovers are functional equivalents (binding to the same epitopes of the same antigens) which may be used for the same purpose, and Tsurushita presents a showing that a bispecific EGFR-targeting antibody may be administered at a flat dosage of 1500 mg for the purpose of treating disease.
Furthermore, in regards to the specific dosages recited in the instant claims, MPEP § 2144.05(II)(A) states, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal therapeutic doses, and one of ordinary skill in the art would have arrived at the dosage of 1500 mg through the process of routine optimization.
(2)
Claims 31, 37-39, 41, 43-44, and 48-49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11,939,394 (supra) in view of Roovers (Cancer Res 2017;77(13 Suppl): Abstract nr 32. doi:10.1158/1538-7445.AM2017-32; supra), Hendrikx (The Oncologist (2017) 22(10): 1212-1221; supra), and Tsurushita (WO 2020/102233 A1; supra) as applied to claims 31, 34, 37, 43, and 47 above, further in view of Wang (Cancer (2007) 109(4): 658-667; supra) and Goletz (US 2016/0068609 A1; supra).
The teachings of the reference patent, Roovers, Hendrikx, and Tsurushita are recited in the 35 U.S.C. § 103 and non-statutory double patenting rejections above.
The reference patent does not expressly claim a method of cancer treatment wherein the method of cancer treatment wherein the cancer is a gastro-esophageal junction cancer, gastric cancer, or esophageal cancer, or that the bispecific antibody is afucosylated. The reference patent also does not claim that the antibody is administered biweekly. However, these deficiencies are remedied by Wang and Goletz.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out the treatment method collectively taught by the reference patent, Roovers, and Hendrikx in a human subject with gastroesophageal junction cancer, gastric cancer, or esophageal cancer. The skilled artisan would have been motivated to do so because Wang teaches that EGFR expression is associated with worse prognostic outcomes in patients with esophageal and EGJ adenocarcinomas. There would have been a reasonable expectation of success because Goletz provides a proof-of-concept that an EGFR-targeting antibody can be administered for treatment of gastric, esophageal, and GEJ cancers.
(3)
Claims 31, 34, 37, 39-41, 43-44, 47-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30, 33-34, 42, 44, 48-51, and 53-59 of co-pending Application No. 17/632,181 (cited in PTO-892) in view of Throsby (US 2018/0312604 A1; supra), Hendrikx (The Oncologist (2017) 22(10): 1212-1221; supra), and Tsurushita (WO 2020/102233 A1; supra).
The co-pending reference application recite methods of treating colorectal cancer and inhibiting proliferation of a cell that expresses EGFR and LGR5, which comprise administering a bispecific antibody comprising the VH of MF3755 (which comprises instant SEQ ID NO: 4), the VH of MF5816 (which comprises instant SEQ ID NO: 13), and a common light chain comprising SEQ ID NO: 113 (which comprises instant SEQ ID NO: 122) (e.g., co-pending claims 30, 42, 44, 49-50, 54-55, and 57-58), pertinent to claims 31 and 47. Co-pending claim 42 recites that the bispecific antibody is afucosylated, relevant to claim 44.
The co-pending claims do not recite that the antibody is administered intravenously at a flat dose of 1500 mg, at weekly, biweekly, or monthly intervals. The co-pending claims also do not teach that the cancer to be treated is gastric cancer or ESCC. However, these deficiencies are remedied by Throsby, Hendrikx, and Tsurushita as set forth in the 35 U.S.C. § 103 rejections above.
Accordingly, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to administer the bispecific antibody taught in the co-pending reference application in a method of treating gastric cancer or ESCC, at a flat dosage of 1500 mg, as determined through the process of routine optimization. The skilled artisan would have been motivated to use a flat dose because Hendrikx teaches that fixed dosage schedules are justified based on pharmacokinetics and furthermore have several advantages, including lower healthcare costs, drug spillage, and medication errors. In addition, Hendrikx notes that the pharmacokinetics of at least one anti-EGFR antibody known in the art (panitumumab) is amenable to a fixed dose regimen. There would have been a reasonable expectation of success because those of ordinary skill in the art would recognize that the bispecific antibodies recited in the co-pending claims and by Throsby are structural and functional equivalents which may be used for the same purpose, and Tsurushita presents a showing that a bispecific EGFR-targeting antibody may be administered at a flat dosage of 1500 mg for the purpose of treating disease.
Furthermore, in regards to the specific dosages recited in the instant claims, MPEP § 2144.05(II)(A) states, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal therapeutic doses, and one of ordinary skill in the art would have arrived at the dosage of 1500 mg through the process of routine optimization.
(4)
Claims 31, 37-39, 41, and 48-49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30, 33-34, 42, 44, 48-51, and 53-59 of co-pending Application No. 17/632,181 (supra) in view of Throsby (US 2018/0312604 A1; supra), Hendrikx (The Oncologist (2017) 22(10): 1212-1221; supra), and Tsurushita (WO 2020/102233 A1; supra) as applied to claims 31, 34, 37, 39-41, 43-44, 47-48 above, further in view of Wang (Cancer (2007) 109(4): 658-667; supra) and Goletz (US 2016/0068609 A1; supra).
The teachings of the co-pending reference application, Throsby, and Hendrikx are recited in the 35 U.S.C. § 103 and non-statutory double patenting rejections above.
The co-pending reference application does not expressly claim a method of cancer treatment wherein the method of cancer treatment wherein the cancer is a gastro-esophageal junction cancer, gastric cancer, or esophageal cancer, or that the antibody is administered biweekly. However, these deficiencies are remedied by Wang and Goletz.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out the treatment method collectively taught by the co-pending claims, Throsby, and Hendrikx in a human subject with gastroesophageal junction cancer, gastric cancer, or esophageal cancer. The skilled artisan would have been motivated to do so because Wang teaches that EGFR expression is associated with worse prognostic outcomes in patients with esophageal and EGJ adenocarcinomas. There would have been a reasonable expectation of success because Goletz provides a proof-of-concept that an EGFR-targeting antibody can be administered for treatment of gastric, esophageal, and GEJ cancers.
(5)
Claims 31, 34, 43-44, and 47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20-28 and 30-33 of co-pending Application No. 18/257,528 (cited in PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims anticipate the instantly claimed invention.
Regarding claims 31 and 47, co-pending claims 20-28 and 30-31 recite a method of treating a head and neck cancer, characterized by expression of LGR5 and/or EGFR, that comprises administering to a human subject in need thereof a flat dose of 1500 mg of an antibody or antigen-binding fragment thereof that comprises a variable domain that binds to an extracellular part of EGFR, having a MF3755 VH comprising an amino acid sequence of SEQ ID NO: 4 (which shares 100% sequence identity to instant SEQ ID NO: 4), a MF5816 VH comprising an amino acid sequence of SEQ ID NO: 13 (which shares 100% sequence identity to instant SEQ ID NO: 13), and the VL of SEQ ID NO: 122 (which shares 100% sequence identity to instant SEQ ID NO: 122).
Regarding claim 34, co-pending claim 22 recites that the antibody is administered intravenously. Regarding claims 43-44, co-pending claims 32-33 recite that the antibody is ADCC-enhanced and afucosylated, respectively.
(6)
Claims 31, 37-41, and 48-49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20-28 and 30-33 of co-pending Application No. 18/257,528 (supra) as applied to claims 31, 34, 43-44, and 47, further in view of Throsby (US 2018/0312604 A1; supra), Wang (Cancer (2007) 109(4): 658-667; supra), and Goletz (US 2016/0068609 A1; supra).
The teachings of the co-pending reference application are recited in the non-statutory double patenting rejection above.
The co-pending reference application does not expressly claim a method of cancer treatment wherein the method of cancer treatment wherein the cancer is a gastro-esophageal junction cancer, gastric cancer, or esophageal cancer, or that the bispecific antibody is administered biweekly. However, these deficiencies are remedied by Throsby, Wang, and Goletz.
Based on the further teachings of Throsby, Wang, Goletz, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out the treatment method collectively taught by the co-pending claims in a human subject with gastroesophageal junction cancer, gastric cancer, or esophageal cancer. The skilled artisan would have been motivated to do so because Wang teaches that EGFR expression is associated with worse prognostic outcomes in patients with esophageal and EGJ adenocarcinomas. There would have been a reasonable expectation of success because Throsby and Goletz provide a proof-of-concept that an EGFR-targeting antibody can be administered biweekly for treatment of gastric, esophageal, and GEJ cancers.
(7)
Claims 31, 34, 37, 39-41, 43-44, and 47-49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 42, 55, 60, and 63 of co-pending Application No. 18/268,168 (cited in PTO-892) in view of Throsby (US 2018/0312604 A1; supra), Hendrikx (The Oncologist (2017) 22(10): 1212-1221; supra), Tsurushita (WO 2020/102233 A1; supra), Wang (Cancer (2007) 109(4): 658-667; supra), and Goletz (US 2016/0068609 A1; supra).
The co-pending reference application recites a pharmaceutical composition comprising a multispecific antibody, functional part, or derivative thereof, comprising an first binding domain that binds to EGFR, comprising a first VH of MF3755 which comprises the amino acid sequence of SEQ ID NO: 5 (which shares 100% sequence identity to instant SEQ ID NO: 4), a second VH that binds to LGR5, comprising a VH of MF5816 which comprises the amino acid sequence of SEQ ID NO: 41 (which shares 100% sequence identity to instant SEQ ID NO: 13), and a VL comprising the amino acid sequence of SEQ ID NO: 53 (which shares 100% sequence identity to instant SEQ ID NO: 122) (e.g., co-pending claims 65, 83-84, and 86).
The reference application does not expressly teach a method of treating a cancer (e.g., a gastric or esophageal cancer) that comprises administering a pharmaceutical composition biweekly at a flat dose of 1500 mg of said multispecific antibody to a human subject. However, this deficiency is remedied by the teachings of Throsby, Hendrikx, Tsurushita, Wang, and Goletz as set forth in the 35 U.S.C. § 103 rejections above.
Taken together, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to administer the pharmaceutical composition taught in the reference patent application in the method of treating a gastric or esophageal cancer, at a flat dosage of 1500 mg as determined through the process of routine optimization. The skilled artisan would have been motivated to use a flat dose because Hendrikx teaches that fixed dosage schedules are justified based on pharmacokinetics and furthermore have several advantages, including lower healthcare costs, drug spillage, and medication errors. In addition, Hendrikx notes that the pharmacokinetics of at least one anti-EGFR antibody known in the art (panitumumab) is amenable to a fixed dose regimen. There would have been a reasonable expectation of success because Throsby teaches that a structurally identical bispecific antibody was well tolerated in toxicity studies, and because those of ordinary skill in the art would recognize that the bispecific antibodies recited in the reference patent and by Throsby are functional equivalents which may be used for the same purpose, and Tsurushita presents a showing that a bispecific EGFR-targeting antibody may be administered at a flat dosage of 1500 mg for the purpose of treating disease.
Furthermore, in regards to the specific dosages recited in the instant claims, MPEP § 2144.05(II)(A) states, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal therapeutic doses, and one of ordinary skill in the art would have arrived at the dosage of 1500 mg through the process of routine optimization.
(8)
Claims 31, 39, 41, and 47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 29-59 of co-pending Application No. 18/431,642 (cited in PTO-892) in view of Hendrikx (The Oncologist (2017) 22(10): 1212-1221; supra) and Tsurushita (WO 2020/102233 A1; supra).
Relevant to claims 31, 39, 41, and 47, co-pending claims 29-31, 37, and 56-59 recite a method of treating a cancer (gastric cancer, colorectal cancer, and others), comprising administering a bispecific antibody comprising a VH that binds to an extracellular part of EGFR (SEQ ID NO: 20), a VH that binds to an extracellular part of LGR5 (SEQ ID NO: 26), and a common VL (SEQ ID NO: 80) which share 100% sequence identity to the respective instantly claimed sequences.
The co-pending reference application does not expressly teach that a flat dosage of 1500 mg of the bispecific antibody is administered in the method of treatment. However, this deficiency is remedied by Hendrikx and Tsurushita as set forth in the 35 U.S.C. § 103 rejections above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the method of treatment taught by the reference application to arrive at a method of treating a cancer that comprises administering a flat dose of 1500 mg of the bispecific antibody, through the process of routine optimization. The skilled artisan would have been motivated to use a flat dose because Hendrikx teaches that fixed dosage schedules are justified based on pharmacokinetics and furthermore have several advantages, including lower healthcare costs, drug spillage, and medication errors. In addition, Hendrikx notes that the pharmacokinetics of at least one anti-EGFR antibody known in the art (panitumumab) is amenable to a fixed dose regimen. There would have been a reasonable expectation of success because those of ordinary skill in the art would have recognized the suitability of the bispecific antibody recited in the reference application for inhibiting EGFR and treating a cancer associated with aberrant EGFR expression, and Tsurushita presents a showing that a bispecific EGFR-targeting antibody may be administered at a flat dosage of 1500 mg for the purpose of treating disease.
Furthermore, in regards to the specific dosages recited in the instant claims, MPEP § 2144.05(II)(A) states, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal therapeutic doses, and one of ordinary skill in the art would have arrived at the dosage of 1500 mg through the process of routine optimization.
(9)
Claims 31, 34, 37-39, 41, 43-44, and 48-49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 29-59 of co-pending Application No. 18/431,642 (supra) in view of Hendrikx (The Oncologist (2017) 22(10): 1212-1221; supra) and Tsurushita (WO 2020/102233 A1; supra) as applied to claims 31, 39, 41, and 47 above, further in view of Wang (Cancer (2007) 109(4): 658-667; supra) and Goletz (US 2016/0068609 A1; supra).
The teachings of the co-pending reference application are recited in the non-statutory double patenting rejection above.
The co-pending reference application does not expressly claim a method of cancer treatment wherein the method of cancer treatment wherein the cancer is a gastro-esophageal junction cancer or esophageal cancer. The co-pending claims also do not recite that the antibody is ADCC-enhanced and/or afucosylated or is administered intravenously at biweekly intervals. However, these deficiencies are remedied by Wang and Goletz as set forth in the 35 U.S.C. § 103 rejection above.
Accordingly, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out the treatment method collectively taught by the co-pending claims in a human subject with gastroesophageal junction cancer or esophageal cancer, wherein the antibody is administered intravenously and biweekly, based on the further teachings of Wang and Goletz. The skilled artisan would have been motivated to do so because Wang teaches that EGFR expression is associated with worse prognostic outcomes in patients with esophageal and EGJ adenocarcinomas. There would have been a reasonable expectation of success because Throsby and Goletz provides a proof-of-concept that an EGFR-targeting antibody can be administered for treatment of gastric, esophageal, and GEJ cancers.
(10)
Claims 31, 37-41, and 47-49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3-7, 9-16, 18, 20, 23, 27, 31, and 36-42 of co-pending Application No. 18/694,252 (cited in PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims anticipate the instantly claimed invention.
Regarding claims 31, 37-41, and 47-49, the co-pending claims recites methods of treating a cancer (e.g., gastric, esophageal, gastric-esophageal-junction, and others) comprising administering 1500 mg of a multispecific antibody that comprises a first variable domain that binds to an extracellular part of EGFR, comprising a first VH comprising the amino acid sequence of SEQ ID NO: 4 (which shares 100% sequence identity to instant SEQ ID NO: 4), a second variable domain that binds to an extracellular part of LGR5, comprising a second VH comprising the amino acid sequence of SEQ ID NO: 13 (which shares 100% sequence identity to instant SEQ ID NO: 13), and a common VL that comprises SEQ ID NO: 122 (which shares 100% sequence identity to instant SEQ ID NO: 122) (e.g., co-pending claims 3-7, 9, 18, 23, 27, 36-41).
Regarding claims 37-38, co-pending claim 20 recites that the antibody or functional part is administered weekly, biweekly, or monthly.
(11)
Claims 31, 34, and 43-44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3-7, 9-16, 18, 20, 23, 27, 31, and 36-42 of co-pending Application No. 18/694,252 (supra) as applied to claims 31, 37-41, and 47-49, further in view of Wang (Cancer (2007) 109(4): 658-667; supra) and Goletz (US 2016/0068609 A1; supra).
The teachings of the co-pending reference application are recited in the non-statutory double patenting rejection above.
The co-pending reference application does not expressly claim that the antibody is ADCC-enhanced and/or afucosylated or is administered intravenously at biweekly intervals. However, these deficiencies are remedied by Wang and Goletz as set forth in the 35 U.S.C. § 103 rejection above.
Accordingly, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out the treatment method taught by the co-pending claims, wherein the antibody is administered intravenously and biweekly (as determined through routine optimization) and further wherein the antibody is ADCC-enhanced and/or afucosylated, based on the further teachings of Wang and Goletz. The skilled artisan would have been motivated to do so because Goletz teaches that antibody afucosylation enhances ADCC mediated by natural killer (NK) cells (e.g., ¶ 0007), which is useful for increasing treatment efficacy. There would have been a reasonable expectation of success because Throsby and Goletz provides a proof-of-concept that an EGFR-targeting antibody with similar properties can be administered in the same manner for treatment of gastric, esophageal, and GEJ cancers.
(12)
Claims 31, 34, 37-38, 43-44, and 47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-12, 15-30, and 37-39 of co-pending Application No. 19/142,031 (cited in PTO-892) as evidenced by Merus News Release (published February 18, 2025; attached in Office Action Appendix mailed September 11, 2025). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims anticipate the instantly claimed invention.
Regarding claims 31, 37-38, and 47, the co-pending reference application recites a bispecific antibody or functional part, derivative and/or analogue thereof that comprises a variable domain that binds an extracellular part of EGFR and a variable domain that binds LGR5, and a method of treating a cancer (e.g., head and neck cancer) in a subject using the same, wherein the bispecific anti-EGFR/anti-LGR5 antibody is petosemtamab2 (e.g., co-pending claims 1-4, 11-12, 14-19, 23, 31, 33, 35). Co-pending claims 9-10 recite that the treated subject is human. Co-pending claim 16 recites that the treatment comprises providing a biweekly dose of 1500 mg of the antibody to the subject in need thereof. Co-pending claims 27-28 provide a kit comprising petosemtamab and instructions for dosing at 1500 mg once every two weeks.
Regarding claim 34, co-pending claim 20 recites that the antibody is provided intravenously. Further regarding claims 43-44, co-pending claims 21-22 recite that the antibody is ADCC-enhanced and afucosylated, respectively.
(13)
Claims 31, 39-41, and 48-49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-12, 15-30, and 37-39 of co-pending Application No. 19/142,031 (supra) as evidenced by Merus News Release (supra) as applied to claims 31, 34, 37-38, 43-44, and 47, further in view of further in view of Throsby (US 2018/0312604 A1; supra), Wang (Cancer (2007) 109(4): 658-667; supra), and Goletz (US 2016/0068609 A1; supra).
The teachings of the co-pending reference application are recited in the non-statutory double patenting rejection above.
The co-pending reference application does not expressly claim a method of cancer treatment wherein the method of cancer treatment wherein the cancer is a gastro-esophageal junction cancer, gastric cancer, or esophageal cancer. However, these deficiencies are remedied by Throsby, Wang, and Goletz.
Based on the further teachings of Throsby, Wang, Goletz, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out the treatment method collectively taught by the co-pending claims in a human subject with gastroesophageal junction cancer, gastric cancer, or esophageal cancer. The skilled artisan would have been motivated to do so because Wang teaches that EGFR expression is associated with worse prognostic outcomes in patients with esophageal and EGJ adenocarcinomas. There would have been a reasonable expectation of success because Throsby and Goletz provide a proof-of-concept that an EGFR-targeting antibody can be administered biweekly for treatment of gastric, esophageal, and GEJ cancers.
(14)
Claims 31, 39-41, 43-44, and 47-49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-54 of co-pending Application No. 19/144,095 as evidenced by Merus News Release (published February 18, 2025; attached in Office Action Appendix mailed September 11, 2025). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims anticipate the instantly claimed invention.
The co-pending claims recite a method of treating a cancer (e.g., gastric, esophageal, or gastroesophageal junction cancer) in a human subject by administering 1500 mg of a bispecific antibody that comprises a MF3755 VH that binds to EGFR and a MF5816 VH that binds to LGR5, wherein the antibody is petosemtamab3, anticipating claims 31, 39-41, and 47-49 (e.g., co-pending claims 2-4, 24-25, 27-31, 33-34). Regarding claims 43-44, the antibody is ADCC enhanced and afucosylated, respectively (e.g., co-pending claims 22-23).
(15)
Claims 31, 34, and 37-38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-54 of co-pending Application No. 19/144,095 as evidenced by Merus News Release (supra) as applied to claims 31, 34, 37-38, 43-44, and 47 above, further in view of Goletz (US 2016/0068609 A1; supra).
The teachings of the co-pending reference application are recited in the non-statutory double patenting rejection above.
The co-pending reference application does not expressly claim that the antibody is administered intravenously at biweekly intervals. However, these deficiencies are remedied by Goletz as set forth in the 35 U.S.C. § 103 rejection above.
Accordingly, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out the treatment method taught by the co-pending claims, wherein the antibody is administered intravenously and biweekly (as determined through routine optimization), based on the further teachings of Goletz. The skilled artisan would have been motivated to do so because Goletz teaches that an alternative anti-EGFR antibody can similarly be administered at a biweekly interval, at a dosage between 1100 mg and 1700 mg, and one of ordinary skill in the art would be motivated to optimize different dosing parameters within their technical grasp. There would have been a reasonable expectation of success because Goletz provides a proof-of-concept that an EGFR-targeting antibody with similar properties can be administered in the same manner for treatment of gastric, esophageal, and GEJ cancers.
Conclusion
No claims are allowed.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643
1 As evidenced by the instant specification (page 50), ES0201 corresponds to an esophageal squamous cell carcinoma.
2 As evidenced by the Merus news release dated February 18, 2025, petosemtamab (MCLA-158) is a Biclonics® low-fucose human full-length IgG1 antibody targeting EGFR and LGR5.
3 As evidenced by the Merus news release dated February 18, 2025, petosemtamab (MCLA-158) is a Biclonics® low-fucose human full-length IgG1 antibody targeting EGFR and LGR5.
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