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 .
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 allowance or after an Office action under Ex Parte Quayle, 25 USPQ 74, 453 O.G. 213 (Comm'r Pat. 1935). 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, prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant's submission filed on 21 October 2025 has been entered.
Status of the Claims
Claims 1-18 were allowed 22 July 2025. Claims 1-18 have been broadened in a request for continued examination received 21 October 2025 and claim 21 has been newly added.
Claim Interpretation
Claim 1 is drawn to an antibody-drug conjugate comprising a heavy chain and light chain. It is noted claim 1 is interpreted as encompassing full length heavy and light chain antibodies and excluding fragments of said heavy and light chains (see specification pg. 14 last para).
Claim 12 is drawn to a method for treating gastric cancer, adenocarcinoma of the
esophagogastric junction, or pancreatic cancer, comprising administering to a subject in need thereof a
therapeutically effective amount of the antibody drug conjugate of claim 1. The specification defines
treating as “generally referring to obtaining a desired pharmacological and/or physiological effect. The
effect may be prophylactic in terms of complete or partial prevention of the disease or its symptoms;
and/or therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects
due to the disease” (see specification pg. 19 lines 11-14). In addition, the specification discloses
treatment encompasses both prevention of disease or symptoms in a patient susceptible to a disease or condition but not yet diagnosed as well as suppression or alleviating the symptoms of the disease (see
specification pg. 19 lines 15-18). It is noted the specification teaches that while treatment encompasses
both prevention and active disease treatment the specification also delineates between a
prophylactically and therapeutically effect amounts. Specifically, the “prophylactically effective amount
will be less than the therapeutically effective amount because the prophylactic dose is administered to
the subject prior to the onset of the disease or at an early stage of the disease. In the case of cancer, the
therapeutically effective amount of the drug reduces the number of cancer cells; shrinks the tumor size;
inhibits (i.e., slows to some extent preferably stops) infiltration of cancer cells into surrounding organs;
inhibits (i.e., slows to some extent, preferably stops) tumor metastasis; inhibits tumor growth in some
degree; and/or alleviates one or more symptoms associated with cancer in some degree” (see specification pg. 19 lines 30-33-pg. 20 lines 1-4). While “treating” recited in line 1 encompasses both
prevention and active disease management the recitation of a “therapeutically effective amount” of the
antibody in line 3 further limits “treating” to subjects with active disease. Therefore, claim 12 is
interpreted as a method of treating gastric cancer, adenocarcinoma of the esophagogastric junction, or
pancreatic cancer wherein the subject has gastric cancer, adenocarcinoma of the esophagogastric
junction, or pancreatic cancer.
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.
Scope of Enablement
Claims 12-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the following:
A method for treating gastric cancer, adenocarcinoma of the esophagogastric junction or pancreatic cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody drug conjugate of claim 21,
does not reasonably provide enablement for:
A method for treating gastric cancer, adenocarcinoma of the esophagogastric junction or pancreatic cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody drug conjugate of claim 1.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized in In re Wands (858 Fed 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, limited working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to make and use the claimed invention.
Breadth of the claims
Claim 12 is drawn to treating 3 different cancers by administering an anti-Claudin 18.2 drug conjugate comprising a particular set of 6 CDRs with any framework region, using any linker, any cytotoxic agent, an antibody drug ratio (DAR) of 2 or more.
Guidance in the specification and working examples
The specification discloses antibodies comprising CDRs from anti-claudin 18.2 antibody 18D10 conjugated via MC-VC-PAB to MMAE with a DARs in the range of 3-4 were effective in eliminating cell line with moderate to highly expressing claudin 18.2 but not in claudin 18.2 negative cell lines (see specification pg. 42 lines 4-9, pgs. 43-44 table 3, pg. 44 lines 7-9). Furthermore, a particular CM311 antibody (i.e., 18D10-VH/VL1-ADC) when conjugated to MC-VC-PAB-MMAE was effective in eliminating KATO III cells while the unconjugated antibody was not (see specification pg. 46 lines 11-14). The disclosure also teaches the particular ADC functions by internalizing into the cells through degradation in the lysosomes releases MMAE (see specification para spanning pags 2-3). Applicant has provided a working example of a CM311 antigen binding domain and a single linker drug combination.
State of the art
The state of the art also teaches the criticality of the linker in efficacy of ADCs as well as the choice of antigen binding domain and payload. Specifically,
“The major hurdle is developing agents with a sufficient therapeutic window between the toxic dose and efficacious dose, and the ADC linker plays a central role in determining both thresholds” (see Knopp and Thurber (2019) Severing ties: quantifying the payload release from antibody drug conjugates. Cell Chemical Biology. Vol. 26, Iss. 12, pgs. 1631-1633, in particular, pg. 1631, 1st col, end of 1st para),
“Alternatively, ineffective linker cleavage (or antibody degradation for non-cleavable linkers) following cell entry can hinder delivery of cytotoxic payload to the site of action. The opposing effect of limiting systemic toxicity while maintaining efficient intracellular payload release remains a major challenge for this field, and optimal combinations of linker and payload are an active area of research to address this obstacle” (see Knopp and Thurber pg. 1631, para spanning cols 2-3),
“While choice of target antigens and pay loads is important, antibody-payload conjugation methods and linker chemistry are also crucial elements for producing successful ADCs. In particular, instability of the linker and heterogeneity of the product (i.e., broad distribution of DARs) often negatively impacts ADC efficacy and therapeutic window, which often leads to difficulty or limitation in the optimization for clinical application and eventual failure in clinical trials” (see Tsuchikama and An (2018) Antibody-drug conjugates: recent advances in conjugation and the linker chemistries. Protein Cell. 9(1): 33-46, in particular pg. 43 cols. 1-2), and
“it is important to identify ADC linkers with optimal linker stability for each combination of antigen, target tumor type, and payload” (see Tsuchikama and An pg. 35 para spanning cols. 1-2).
Therefore, the ordinary artisan would understand the choice of antigen binding domain, linker, and payload are all critical to the overall efficacy of an antibody drug conjugate and the particular combinations can have unpredictable outcomes (e.g., increased clearance). Applicant’s disclosure of a single art recognized linker drug combination is not representative or predictive of the breadth of the genus.
Conclusion
Accordingly, in the absence of substantive direction or guidance in the instant specification, the entire scope of experimentation required to develop antibody drug conjugates that treat gastric cancer adenocarcinoma of the esophagogastric junction or pancreatic cancer comprising an anti-claudin 18.2 antibody with particular CDRs and any framework region, DAR, linker, and drug combination is left to those skilled in the art, the present claims and disclosure amounting to nothing more than an invitation to the skilled artisan to invent such combinations. Given the resource intensive nature of the required experimentation, the skilled artisan would reasonably conclude that such experimentation would be unnecessarily and improperly extensive and undue.
Written Description
Claims 12-18 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.
Claim 12 is drawn to treating 3 different cancers by administering an anti-Claudin 18.2 drug conjugate comprising a particular set of 6 CDRs with any framework region, using any linker, any cytotoxic agent, an antibody drug ratio (DAR) of 2 or more.
Applicant discloses antibodies comprising CDRs from anti-claudin 18.2 antibody 18D10 conjugated via MC-VC-PAB to MMAE with a DARs in the range of 3-4 were effective in eliminating cell line with moderate to highly expressing claudin 18.2 but not in claudin 18.2 negative cell lines (see specification pg. 42 lines 4-9, pgs. 43-44 table 3, pg. 44 lines 7-9). Furthermore, a particular CM311 antibody (i.e., 18D10-VH/VL1-ADC) when conjugated to MC-VC-PAB-MMAE was effective in eliminating KATO III cells while the unconjugated antibody was not (see specification pg. 46 lines 11-14). The disclosure also teaches the particular ADC functions by internalizing into the cells through degradation in the lysosomes releases MMAE (see specification para spanning pags 2-3). Applicant has provided a limited number of working examples of a CM311 antigen binding domain (i.e., a particular set of CDRs) and a single linker drug combination. The disclosed species are no sufficiently representative of the genus of different linker, drug, and DAR encompassed by the claims.
The state of the art teaches not all cytotoxic agents can be used in antibody drug conjugates.
“In summary, CFZ is a potent cytotoxic agent in various cancer cell lines; however, CFZ is an inactive payload in ADCs. Our studies demonstrated that CFZ is highly vulnerable to hydrolysis in lysosomal fractions. CFZ conjugated to antibodies loses its cytotoxic potency because of the extensive hydrolysis of the drug occurring in lysosomes, which is necessary for ADC catabolism. The results indicate that when selecting an appropriate payload in the development of an ADC, lysosomal stability is a property of payloads that should be taken into consideration” (see Ma et al. (2019) Carfilzumib is not an appropriate payload of antibody drug conjugates due to rapid inactivation by lysosomal enzymes, Drug Metab Dispos Vol. 47, Iss. 8, pgs. 884-889, in particular para spanning pgs. 888-889).
The state of the art also teaches particular linkers and DAR can have negative impacts on ADC function and therefore efficacy in the treatment of cancer let alone particular cancers. Specifically,
“The earlier ADCs, such as BR96-DOX and Mylotarg@, did not have a sufficient therapeutic index and had been withdrawn from the market, which was attributed to the poor stability of linkers” (see Lu et al. (2016) Linkers having a crucial role in antibody drug conjugates. Int. J. Mol. Sci, (17)4: 561 in particular pg. 5, 1st para) and
“DAR constitutes a major concern for designing ADC therapeutics, since DAR tightly impacts the aggregation propensity, in vivo potency and serum stability of ADC. ADC with high DAR usually has higher aggregation propensity due to the increased hydrophobicity conferred by the hydrophobic drug molecules. Guo et al. have found that their ADC with DAR6 species may exist in a multimeric state, while DAR2 and DAR4 species likely exist in monomeric forms under ambient conditions. Beckley et al. have reported that their ADC Antibodies aggregate mainly contained the high DAR species of 6–8. Meanwhile, ADC with high DAR was reported to be subjected to more structural perturbations, causing the destabilization of mAb, as exampled by Adem et al. showing that high DAR species readily experienced aggregation and fragmentation under stress conditions, such as high ionic strength buffer, due to the fewer inter-chain disulfide bonds. The destabilized structure of high DAR species could probably reconcile its fast plasma clearance when encountered with protease degradation” (see Li et al. (2016) Antibody aggregation: insights from sequence and structure. Antibodies 5, 19, pgs. 1-23, in particular, para spanning pgs. 13-14).
Therefore, the ordinary artisan would understand the combination of the particular linker and drug chosen as well as the DAR are critical in the overall efficacy of an ADC. Modifications to these structures and attribute can render an ADC ineffective in treating cancer let alone a particular cancer. It would be impossible for one of ordinary skill in the art to predict which linker drug combinations with which DARs will effectively treat the instantly claimed cancers.
New Matter
Claims 1-3 and 11-18 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.
Claim 1 is drawn to an anti-claudin 18.2 antibody drug conjugate wherein the antibody drug ration (DAR) is “at least 2.0” (see claim 1 last line). The specification does not disclose or contemplate a genus of anti-claudin 18.2 drug conjugates with a DAR above 8 (see specification pg. 2 lines 24-25, pg. 9 lines 7-10). Therefore reciting a genus of anti-claudin 18.2 drug conjugates with a DAR above 8 reaches beyond the specification as originally filed.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 7, 8, 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.
The term “about” in claims 7 and 8 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. For example, it is unclear when a DAR is about 3.0 versus about 3.4.
Double Patenting
Statutory Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claims 4-8 are provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 8 and 18-21 of copending Application No. 18/031,731 (referred to herein as ‘731 application). This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented.
Non-Statutory 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.
Claims 1-15, 17, 18 and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-5, 9, and 19-33 of copending Application No. 17/604735 (referred to herein as ‘735 application) and Kamath and Iyer (see Kamath and Iyer (2015) Preclinical Pharmacokinetic considerations for the development of antibody drug conjugates. Pharm Res Vol. 32, pgs. 3470-3479). Although the claims at issue are not identical, they are not patentably distinct from each other.
The ‘735 application claims an anti-human claudin 18.2 comprising Seq ID No: 231 and VL Seq ID No: 261 comprising the claimed CDRs (see ‘735 application claims 2, 3, 23 and 24).
Alignment of instant Seq ID No: 65 and ‘735 application Seq ID No: 231 (VH)
PNG
media_image1.png
244
722
media_image1.png
Greyscale
Alignment of instant Seq ID No: 66 and ‘735 application Seq ID No: 261 (VL)
PNG
media_image2.png
242
716
media_image2.png
Greyscale
The ‘731 application claims a conjugate comprising the claimed binding region conjugated to a cytotoxic drug (see ‘731 application claim 9 and 27). In performing the NSDP analysis, the first question to be asked is whether any examined claim is either anticipated by, or obvious over, a claim in the copending application. MPEP 804 (II)(B), second paragraph. While normally one cannot look into the specification of that copending application, it is in fact appropriate to learn which particular embodiments the claims cover. 804(II)(B)(1). The ‘731 specification discloses “coupling (i.e., physically linking) a detectable substance to the antibody” (see ‘731 specification pg. 31, top). Therefore the ordinary artisan would have found it obvious to “link” the cytotoxic moiety to the antibody. In addition the ‘731 application claims a method of treating gastric cancer in a mammal by administering the claimed agent (see ‘731 application claim 19).
Kamath and Iyer disclose ADC with lower drug loads (i.e., DAR of 2 or 4) had “slower clearance values, longer half-lives, and were better tolerated in mice compared to an ADC with a higher drug load (i.e., DAR of 8)” (see Kamath and Iyer pg. 3475, 2nd col. 2nd para). In addition, Kamath and Iyer disclose MC-VC-PAB-MMAE is one of three linker drug combinations well known and clinically validated (see Kamath and Iyer pg. 3474, 2nd col. 2nd para). Therefore the ordinary artisan would have found it obvious to conjugate the MC-VC-PAB-MMAE to the antibody with a DAR of 2.0-4.0 as taught by Kamath and Iyer to the anti-claudin 18.2 antibody as claimed in the ‘731 application given the therapeutic advantages taught by Kamath and Iyer.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-18 and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 7, 9-12, 24, and 26 of copending Application No. 18/927,411 (referred to herein as ‘411 application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The ‘411 application claims a method of treating cancer by administering a human anti-claudin 18.2 ADC comprising identical CDRs, VH and VL sequences conjugated to MMAE via a linker (see ‘411 application claims 1-3).
Alignment of instant Seq ID No: 65 and ‘411 application Seq ID No: 7 (VH)
PNG
media_image3.png
290
715
media_image3.png
Greyscale
Alignment of instant Seq ID No: 66 and ‘411 application Seq ID No: 8 (VL)
PNG
media_image4.png
278
717
media_image4.png
Greyscale
Dependent claims recite wherein the linker is MC-VC-PAB (see ‘411 claim 9), the DAR is an average of 3.8 (see ‘411 claim 12), and the particular cancers treated are gastric, gastroesophageal junction, or pancreatic cancer (see ‘411 claim 26).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HILARY ANN PETRASH whose telephone number is (703)756-4630. The examiner can normally be reached Monday-Friday 8:30-4:30 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at (571)-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/H.A.P./Examiner, Art Unit 1644
/AMY E JUEDES/Primary Examiner, Art Unit 1644
Prosecution Insights