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
Status of Application, Amendments, and/or Claims
Applicant's amendment filed on 06/16/2026 has been entered. Claims 37, 47, and 58 are amended. Claims 89-111 are added. Claims 37, 47, 58, and 89-111 are pending and currently under consideration.
Withdrawn Objections and/or Rejections
The rejection of claims 37 and 47 under 35 U.S.C. 112(b) for reciting a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) is withdrawn in view of amended claims.
The objection to claim 37 is withdrawn in view of amended claim.
Claim Rejections under 35 USC § 112 (a)
(i). 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.
(ii). Claims 37, 47, and 58 are rejected under 35 U.S.C. 112(a), 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 at the time the application was filed, had possession of the claimed invention. The basis for the rejection is set forth in the office action mailed on 06/16/2026. New claims 89-109 are also rejected on the same basis.
(iii). Response to Applicant’s argument
Applicant notes that in Teva Pharmaceuticals Int'l GmbH v. Eli Lilly & Co. (Fed Cir. 2026) the Federal Circuit upheld broad method-of-treatment claims reciting administering "an anti-CGRP antagonist antibody" to treat headache, even though the claims covered any antibody satisfying that functional requirement. Applicant notes that for method claims, the court held that the written description and enablement inquiries under 35 U.S.C. § 112 focus on the claimed use-not the genus of antibodies themselves.
Applicant argues that similar to the claims at issue in Teva v. Eli Lilly, present independent claims 37 and 58 are not drawn to a genus of anti-Claudin-8.2 antibodies themselves, but rather to use of RNA encoding such anti-Claudin-18.2 antibodies to treat CLDN-18.2-positive solid tumors. Applicant argues that various exemplary antibodies that may be used are clearly described in Applicant's specification (see e.g., paragraphs [130]-[150]) and that Applicant's specification provides adequate written description support for claims 37 and 58.
Applicant’s argument has been fully considered but is not deemed to be persuasive. The fact pattern in the instant case is different from that in Teva Pharmaceuticals Int'l GmbH v. Eli Lilly & Co. (Fed Cir. 2026). In Teva Pharmaceuticals v. Eli Lilly & Co. (Appeal No. 24-1094), the claim methods of treating headaches in a human comprising administering to the human an effective amount of an anti-CGP antagonist antibody, wherein said anti-CGRP antagonist antibody is a humanized monoclonal antibody. The specification explains that anti-CGP antagonist antibodies were known in the art and discloses one humanized anti-CGRP antagonist antibody as well as various murine anti-CGRP antagonist antibodies. In contrast, claim 37, for example, of the instant application is drawn to “a method comprising administering a pharmaceutical composition to a subject suffering from a CLDN-18.2-positive solid tumor, thereby treating the subject, wherein the pharmaceutical composition comprises (a) at least one single-stranded RNA comprising one or more coding regions that encode an antibody agent that binds preferentially to a Claudin-18.2 (CLDN-18.2) polypeptide relative to a Claudin-18.1 (CLDN-18.1) polypeptide; …”. There is no functional limitation for the CLDN-18.2 antibody. It is known in the art that an antibody may be an antagonist antibody or an agonist antibody. If a CLDN-18.2 antagonist antibody is useful for treating a CLDN-18.2-positive solid tumor, a CLDN-18.2 agonist antibody cannot be used for treating a CLDN-18.2-positive solid tumor. Moreover, there is no evidence on the record showing that CLDN-18.2 antibodies that bind preferentially to a Claudin-18.2 (CLDN-18.2) polypeptide relative to a Claudin-18.1 (CLDN-18.1) polypeptide are well-known in the art. Therefore, the instant disclosure does not adequately support the genus of the recited antibodies and thus the method of using the same.
Claim Rejections under 35 USC § 112 (b)
(i). 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.
(ii). Claims 37, 47, 58, 110 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.
(i). Claims 37, 58, and 110-111 recite “… an antibody agent that binds preferentially to a Claudin-18.2 polypeptide relative to a Claudin-18.1 (CLDN-18.1) polypeptide”. The term “preferentially” in claims is a relative term which renders the claims indefinite. The term “preferentially” is not defined by the claims, 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.
(ii). Claims 37 and 110 are drawn to a method comprising administering a pharmaceutical composition to a subject suffering a CLDN-18.2-positive solid tumor, thereby treating the subject. Claims 37 and 110 are indefinite because they do not particularly point out and distinctly claim the subject matter. Applicant argues that claim 37 is amended to recite “thereby treating the subject”. This is not persuasive because a subject may suffer additional conditions or diseases in addition to a CLDN-18.2-positive solid tumor. Claim 37 does not point out the particular disease to be treated. The following amendment is suggested for clarity: a method of treating a CLDN-18.2-positive solid tumor in a subject comprising administering a pharmaceutical composition to said subject.
(iii). Claims 58 and 111 read: “In a method of delivering a CLDN-18.2-targeting antibody for cancer treatment in a subject, the improvement comprising administering to the subject a pharmaceutical composition…”. It is unclear what the improvement referred to, there is insufficient antecedent basis for this limitation in the claims. Applicant argues that it is clear that the improvement refers to delivery of a CLDN-18.2-targeting antibody. This is not persuasive for the reasons set forth above.
Claim Rejections under 35 USC § 103(a)
(i). 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.
(ii). Claims 37, 47, 58, and 89-111 are rejected under 35 U.S.C. 103(a) as being unpatentable over Tran et al. (EMBO 9 (10), 1434-1447, 2017) in view of Türeci et al. (Oncoimmunology, Vol. 8, No. 1, e1523096, 10 pages, published online, 10 Nov 2018) or US 9,751,934 B2 (Date of Patent: Sep. 5, 2017).
Tran et al. teach a pharmaceutical composition comprising mRNA that encodes an antibody and lipid nanoparticles (see, e.g., Abstract). Tran et al. teach that various antibodies using different designs were expressed and characterized in vitro and in vivo in the fields of cancer immunotherapies and that therapeutic mRNA‐mediated antibody expression allowed mice to survive an otherwise lethal tumor challenge (Abstract). Tran et al. teach that intravenous injection of mRNA-LNP encoding Rituximab protects mice from lethal tumor challenge (Fig. 5).
Tran et al. do not teach a pharmaceutical composition comprising a single-stranded RNA encoding an antibody that specifically binds Claudin-18.2 and lipid nanoparticles and a method comprising administering the composition to a subject suffering from a CLDN-18.2-positive solid tumor.
Türeci et al. teach a monoclonal antibody, zolbetuximab, which has been generated against Claudin-18.2 (CLDN18.2). Türeci et al. suggest further clinical development of zolbetuximab to patients with CLDN18.2-expressing pancreatic cancer (see, e.g., Abstract). Türeci et al further teach that in a phase 2 clinical trial, zolbetuximab in conjunction with chemotherapy prolonged overall progression-free survival over chemotherapy and improved quality of life (see, e.g., Abstract).
US 9,751,934 B2 teach a monoclonal antibody against CLDN-18.2 for treatment of cancer, said antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 118 and a light chain amino acid sequence of SEQ ID NO: 125, which comprise the six CDR amino acid sequences and correspond to the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2 of the present application, respectively, as acknowledged in the instant specification (page 45, paragraph [134]).
It would have been obvious to one having ordinary skill in the art at the time the invention was made to make a pharmaceutical composition comprising a single-stranded RNA encoding an anti-Claudin-18.2 antibody taught by either Türeci et al. or US 9,751,934 B2 and lipid nanoparticles, and to treat a CLDN-18.2-positive solid tumor with a reasonable expectation of success. One would have been motivated to do so because such a pharmaceutical composition allows expression of the encoded antibody without inducing an adverse immune response against the encoded antibody as taught by Tran et al. (Abstract).
It would also have been obvious to one having ordinary skill in the art at the time the invention was made to administer to a subject a pharmaceutical composition taught by Tran et al. and Türeci et al. in combination with a chemotherapeutic agent with a reasonable expectation of success. One would have been motivated to do so because such a combination therapy with chemotherapeutic agent is well-known in the art and routinely practiced by one of skill in the art. Claims 93, 90-91, 93, 95-99, and 101-109 recites particular patient population, dosage, or treatment regimen. However, all are routinely practiced by one of skill in the art.
(iii). Response to Applicant’s argument
At the 3rd paragraph of page 14 of Applicant’s response filed on 06/16/2026, Applicant argues that Appendix Table S1 of Thran et al. reports an increase in cytokines TNF and IL-6 and that Tnreci et al. do not assess delivery of mRNA by LNP at all. Applicant argues that given these findings of Thran et al., contrary to the position taken by the Office Action, one of ordinary skill in the art would not have been motivated to make a pharmaceutical composition comprising a single-stranded RNA encoding an anti-Claudin-18.2 antibody and lipid nanoparticles, at least with a reasonable expectation of success.
Applicant’s argument has been fully considered but is not persuasive. On page 1437, 1st paragraph of left column, Tran et al. state the following:
In addition, mice were analyzed for general tolerability of mRNA‐LNP treatment. We did not observe any adverse events throughout the present studies. There was a transient weak increase of some cytokines in circulation (Appendix Table S1), which obviously did not hamper high protein expression. Of note, equal or even higher levels were considered unproblematic in a recent study on modified mRNA encoding factor IX (Ramaswamy et al, 2017). Histopathology of liver, the target organ of mRNA‐LNPs, did not reveal any signs of abnormality or inflammation (Appendix Fig S9). In summary, we could demonstrate that mRNA‐LNP enables a rapid and strong expression of mRNA‐encoded mAbs and VNAs. Moreover, sustained protein availability was not compromised by in situ expression via mRNA.
From the above statement, it is clear that Tran et al. did not observe any adverse events throughout the present studies. While there was a transient weak increase of cytokines TNF and IL-6 in circulation, it obviously did not hamper high protein expression. Tran et al. further state that equal or even higher levels were considered unproblematic in a recent study on modified mRNA encoding factor IX (Ramaswamy et al, 2017). Histopathology of liver, the target organ of mRNA‐LNPs, did not reveal any signs of abnormality or inflammation (Appendix Fig S9). Therefore, in view of the teachings of the cited art, it would have been obvious to one having ordinary skill in the art at the time the invention was made to make a pharmaceutical composition comprising a single-stranded RNA encoding an anti-Claudin-18.2 antibody taught by Türeci et al. or US 9,751,934 B2 and lipid nanoparticles, and to treat a CLDN-18.2-positive solid tumor with a reasonable expectation of success.
Beginning at the 3rd paragraph of page 15 of Applicant’s response filed on 06/16/2026,
Applicant submits that based on the cited references, a person of ordinary skill in the art would not have a reasonable expectation that RNA encoding an antibody agent that binds preferentially to CLDN-18.2 could even be used to treat a subject suffering from a CLDN-18.2-positive solid tumor, as recited in the pending claims. Thran et al. reported testing mRNA-LNP encoding rituximab and "mRNA-LNPs coding for an irrelevant antibody were used as further control" (at page 1440, col. 2). Although Thran reported anti-tumor effect of mRNA- LNP for rituximab, "[a]nimals treated with irrelevant antibody mRNA appeared to show delayed tumor growth kinetics" (at page 1440, col. 2). Thus, at least some anti-tumor effects were not attributed to the relevant antibody (rituximab). Tnreci does not disclose delivery of mRNA by LNP. As such, one of ordinary skill in the art would not have had a reasonable expectation that RNA encoding an antibody agent that binds preferentially to CLDN-18.2 could even be used specifically to treat a subject suffering from a CLDN-18.2-positive solid tumor, as recited in the pending claims.
Applicant’s argument has been fully considered but is not persuasive. On page 1440, 1st paragraph of right column, Tran et al. state the following:
Animals treated with irrelevant antibody mRNA appeared to show delayed tumor growth kinetics. This effect may be attributable to the aforementioned weak cytokine response and/or repeated injections/handling per se. Nevertheless, even compared to this control group, treatment with recombinant antibody at a dose which has been widely used in mouse studies on rituximab clearly suppressed tumor growth. The anti‐tumor effect of 50 μg of mRNA‐LNP for rituximab was even more pronounced and as strong as in the first study. In summary, mRNA‐encoded antibodies appear to represent a viable therapeutic option for various biological threats, including (viral) infections, intoxication, and cancer.
Tran et al. conclude that mRNA‐encoded antibodies appear to represent a viable therapeutic option for various biological threats, including cancer. Thus, one of ordinary skill in the art would have had a reasonable expectation that RNA encoding an anti-CLDN-18.2 could be used to treat a CLDN-18.2-positive solid tumor in a subject
Beginning at the 1st paragraph of page 16 of Applicant’s response filed on 06/16/2026,
Applicant argues that the Office Action's assertion that it would have been obvious to combine Thran et al. with Tnreci et al. to provide an mRNA-LNP encoding a CLDN18.2-targeting antibody for the treatment of a CLDN18.2-positive solid tumor, is based on an over simplified view of the underlying biology, and does not adequately support the asserted reasonable expectation of success. Applicant argues that the Office Action's analysis erroneously treated liver-mediated expression of a CLDN18.2-targeting antibody following mRNA-LNP administration as a straightforward substitute for intravenous administration of the recombinant antibody, without addressing whether the skilled person would reasonably have expected these fundamentally different delivery modalities to provide comparable therapeutic exposure at a solid epithelial tumor.
Applicant argues that the Office Action's reasoning assumed that a CLDN18.2-targeting antibody, known to be effective when administered intravenously, would likewise be expected to provide therapeutic benefit if produced endogenously following administration of an mRNA-LNP formulation.
Applicant’s argument has been fully considered but is not persuasive because Tran et al. have demonstrated in vivo expression of mRNA‐LNP encoded antibody following
intravenous injection of mRNA-LNP encoding antibody (Figure 3) and protection of mice from lethal tumor challenge following intravenous administration of mRNA-encoded mAb Rituximab (Figure 5). In view of the combined teachings of the cited art, it would have been obvious to one having ordinary skill in the art at the time the invention was made to make a pharmaceutical composition comprising a single-stranded RNA encoding an anti-Claudin-18.2 antibody taught by Türeci et al. or US 9,751,934 B2 and lipid nanoparticles, and to treat a CLDN-18.2-positive solid tumor with a reasonable expectation of success. Therefor the rejection is maintained.
Sequence Compliance
This application contains sequence disclosures that are encompassed by the definitions for amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 because not all the amino acid sequences present in the specification (see page 45, paragraph [133]) have been identified with a SEQ ID NO
All the amino acid sequences appearing in the specification must be identified by a sequence identifier in accordance with 37 C.F.R. 1.821(d). Applicants must provide appropriate amendments to the specification inserting the required identifiers. If the amendments are extensive then a substitute specification may be required.
Conclusion
No Claims are allowed.
Advisory Information
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Primary Examiner, Art Unit 1674
August 1, 2026
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