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
Election/Restrictions
Applicant’s election without traverse of Group I, claims 16-34 and species: metastatic nasopharyngeal carcinoma, CCND1, toripalimab, antibody in combination with gemcitabine and cisplatin, a fixed dose of 240 mg, 1000 mg/m^2 body surface area, 80 mg/m^2 body surface area, and once every three weeks in the reply filed 12/15/2025 is acknowledged.
Claims 35-36 are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions and species, there being no allowable generic or linking claims. Election was made in the reply filed 12/15/2025.
Claims 16-19, 21, 23-34, and new claims 37-38 are under consideration in the instant Office Action.
Withdrawn rejections
Rejections of claims 16-25 and 30-31 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paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter are hereby withdrawn in view of amendments to the claims.
Rejections of claims 16-34 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating nasopharyngeal carcinomas using toripalimab in combination with gemcitabine and cisplatin, does not reasonably provide enablement for preventing nasopharyngeal carcinomas with any anti-PD-1 antibody in combination with gemcitabine and cisplatin are hereby withdrawn in view of amendments to the claims.
Modified Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 23-24 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.
The language of claims 23-34 broadens the scope of what is encompassed by the sequences recited. As such, the claim is directed to an antibody defined by function (binding). See MPEP §2163(I)(A) which states:
"The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art recognized correlation or relationship between the structure of the invention and its function. A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.”
Instant claims 23-24 recite the heavy and light chain variable region and heavy and light chain sequences of the antibody that binds to PD-1 with the terminology “an amino acid as set forth in”. There is no limitation or exclusion in the claim language that prevents the modifications from occurring within the CDR region due to the claim language of “an amino acid set forth in”, which widens the scope of the claim to encompass an immense number of unknown molecules that share some identity to the claimed sequences and can bind to the claimed receptor. Applicant has not demonstrated that they are in possession of all the molecules that fall within the immense scope of the claim that are able to achieve the claimed function.
The use of “an amino acid sequence set forth in” can be interpreted as comprising the whole sequence or only comprising some of the amino acids contained within the sequence. As currently recited, the language of “an amino acid sequence” reads on less than the amino acids listed in the sequence identity number that are capable of binding to any isolated antigen. The minimum requirement of any sequence that would meet the limitations of the claim as written only requires a few amino acids in common with the claimed sequence. There is a lack of support for all of the potential amino acid sequence as claimed that is capable of binding to any antigen as written. Applicant is encouraged to amend the claim language to “… regions comprising the amino acid sequence of SEQ ID NO: … ” in the instant claims to obviate this rejection.
Therefore, claims 23-24 do not meet the written description requirement.
Response to Arguments
Applicant's arguments filed 07/21/2026 have been fully considered but they are not persuasive.
Applicant argues that the claims with the noted recitations were either cancelled or amended to remove recitations of “an amino acid”. These changes are found in claim 34; however, instant claim 23-24 were not amended to address the issue regarding the language.
As such, the rejection is maintained.
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.
Claims 16-19, 21, 23-34, and new claims 37-38 are rejected under 35 U.S.C. 103 as being unpatentable over Wei et al. (in PTO-892 filed 04/21/2026), in view of Zhang et al. 2016 (in PTO-892 filed 04/21/2026), and Keam et al. 2019 (in PTO-892 filed 04/21/2026).
Regarding instant claim 16, Wei et al. discloses the results of a phase I study of toripalimab in patients with refractory malignant solid tumors, and that the eligible patients “were diagnosed with treatment-refractory, stage IV malignant tumors at enrollment. The cancer types they suffered from included nasopharyngeal carcinoma (6/25, 24.0%), …, pharyngeal squamous cell carcinoma (1/25, 4.0%), … Additionally, 16 (64.0%) patients had at least 2 prior lines of chemotherapy. Until data cut-off time of 24th January 2018, the median treatment period was 57 days (range: 1-550 days).The median dose intensity explored was 1.500 mg/kg/week (range: 0.128-5.000 mg/kg/week). The median follow-up time was 5.0 months (range: 1.5-19.8 months)”, see page. 349.
Regarding instant claim 17, Wei et al. teaches that the eligible patients were “adults with histologically confirmed, treatment-refractory, advanced, solitary malignant tumors”, see Abstract.
Regarding instant claims 18 and 19, Wei et al. also teaches that the cancers had positive PD-L1 expression, denoting through immunohistochemical staining analysis that they found “a positive PD-L1 expression was defined as ≥5% membrane staining of any intensity on tumor cells or tumor-infiltrating immune cells”, see page 348.
Regarding instant claims 16, 23-24, and 34, Wei et al. teaches the antibody referred to as “toripalimab” which is the same antibody as recited in the instant invention and encompasses instant SEQ ID NOs: 1-10. The instant specification discloses on pages 5-6 that the sequences SEQ ID NOs: 1-10 belong to the antibody known as “toripalimab”.
Regarding instant claim 26, Wei et al. teaches that “toripalimab was intravenously infused every 2 weeks in dose-escalating cohorts at 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, and 240 mg. The study followed standard 3 + 3 design”, see Abstract.
Wei et al. also postulates future uses of the anti-PD-1 antibody, “which was well tolerated and demonstrated anti-tumor activity in treatment-refractory advanced solitary malignant tumors”, see page 352. Wei et al. also recommends further exploration in various tumors and combination therapies, see page 352.
However, Wei et al. does not explicitly recite combination therapies with gemcitabine and cisplatin. Zhang et al. remedies this deficiency.
Zhang et al. teaches that outcomes are poor for patients with recurrent or metastatic nasopharyngeal carcinoma, and compares the “efficacy and safety of gemcitabine plus cisplatin versus fluorouracil plus cisplatin in patients with recurrent or metastatic nasopharyngeal carcinoma”, see Abstract.
Regarding instant claim 16, the patient eligibility criteria included “patients with histologically or cytologically confirmed nasopharyngeal carcinoma. The histological subtype of nasopharyngeal carcinoma was categorised according to the WHO classification of tumours. Type I is keratinising squamous-cell carcinoma. Type II is differentiated non keratinising carcinoma. Type III is undifferentiated non keratinising carcinoma”, see Methods.
Regarding instant claims 27-33 and new claims 37-38, Zhang et al. teaches “patients with recurrent or metastatic nasopharyngeal carcinoma were recruited from 22 hospitals in China. ... Patients were randomly assigned in a 1:1 ratio to receive either gemcitabine (1 g/m2 intravenously on days 1 and 8) and cisplatin (80 mg/m2 intravenously on day 1), or fluorouracil (4 g/m2 in continuous intravenous infusion over 96 h) and cisplatin (80 mg/m2 on day 1 given intravenously) once every 3 weeks for a maximum of six cycles… The primary endpoint was progression-free survival assessed by the independent image committee in the intention-to-treat population”, see Methods.
Zhang et al. found that “the median progression-free survival was 7·0 months (4·4-10·9) in the gemcitabine group and 5·6 months (3·0-7·0) in the fluorouracil group (hazard ratio [HR] 0·55 [95% CI 0·44-0·68]; p<0·0001)” and concluded that “gemcitabine plus cisplatin prolongs progression-free survival in patients with recurrent or metastatic nasopharyngeal carcinoma. The results establish gemcitabine plus cisplatin as the standard first-line treatment option for this population”, see Interpretation under Summary.
However, Wei et al. and Zhang et al. do not teach about the role of the Epstein-Barr virus in nasopharyngeal carcinomas. Keam et al. remedies this deficiency.
Keam et al. teaches that the recommended dosage for toripalimab is “3 mg/kg every 2 weeks as an intravenous (IV) infusion until disease progression or unacceptable toxicity”, see Introduction. Keam et al. teaches the use of toripalimab in patients with “refractory or metastatic nasopharyngeal carcinoma who had experienced progression after standard therapy, treatment with IV toripalimab 3 mg/kg every 2 weeks in a phase 2, open-label trial conducted in China (NCT02915432) achieved an ORR of 30.8% (16 partial responses) and a DCR of 61.5% (n = 52 evaluable patients as at January 2018) [15]. ORR in PD-L1 positive tumours was 38.5%”, see page 576.
Regarding instant claim 21, Keam et al. report an “average 47-fold reduction in plasma Epstein Barr virus DNA copy number was seen in patients who responded to treatment with toripalimab”, see page 576.
It would be obvious at the time of the instant invention to use the antibody and dosage regimens taught by Wei et al., which is an effective treatment against nasopharyngeal carcinomas that results in a durable response rate in afflicted patients, with the combination therapy taught by Zhang et al. which treats nasopharyngeal cancers that have failed previous chemotherapy, or require a multifaceted combinatorial approach to targeting cancer cells, with the teachings of Keam et al. which elucidate the role of the Epstein Barr virus in the origins of the cancer. One would be motivated to combine the antibody and dosage regimen, with the additional chemotherapeutics of gemcitabine and cisplatin, with the expectation of treating the cancers effectively. Wei et al. proposes further exploration in various tumors and combination therapies, and Zhang et al. address this common goal by providing further therapeutic options that are proven to be effective against nasopharyngeal carcinomas that are refractory in nature. A person of ordinary skill in the art would have been motivated to combine treatment modalities known to be useful for the same conditions, and would have expected the combination therapy to be at least as good as either therapy alone (see MPEP §2144.06).
The instant claims are amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose (e.g., treating nasopharyngeal carcinomas) in order to form a third composition that is to be used for the very same purpose since the idea of combining them flows logically from their having been individually taught in the prior art. Applying the same logic to the instant claims, given the teachings of the prior art, it would have been obvious to combine the treatments because the idea of doing so would have logically followed from their having been individually taught in the prior art to be useful as anti-cancer agents. One of ordinary skill in the art would have reasonably expected to obtain a therapeutic benefit upon the combination of the agents since they had been demonstrated in the prior art to be reasonably predictive of treating nasopharyngeal carcinomas.
Therefore, claims 16-19, 21, 23-34, and new claims 37-38 are rejected as obvious over Wei et al., Zhang et al., and Keam et al.
Response to Arguments
Applicant's arguments filed 07/21/2026 have been fully considered but they are not persuasive.
Applicant argues that there is no reasonable expectation of success because “none of Wei, Zhang, and Kearn discloses keratinizing nasopharyngeal carcinomas” and that “a drug effective against recurrent or metastatic NPC primarily targets a disease stage, not a specific histology”. This is not found persuasive.
The teachings of Zheng et al. show that the patient eligibility criteria for their treatment included “patients with histologically or cytologically confirmed nasopharyngeal carcinoma. The histological subtype of nasopharyngeal carcinoma was categorized according to the WHO classification of tumour. Type I is keratinizing squamous-cell carcinoma. Type II is differentiated non keratinizing carcinoma. Type III is undifferentiated non keratinizing carcinoma”, see Methods. As such, the prior art reference do consider and teach the limitations regarding keratinizing nasopharyngeal carcinomas. Additionally, the combination of references also teaches that the toripalimab, which is an anti-PD-1 antibody, is the primary drug used in these treatments. This is mirrored and recited in the instant claims, where the cancer is targeted by its overexpression of PD-1 (disease stage) by the immunotherapeutic. Other known chemotherapeutics such as gemcitabine and cisplatin are added as additional therapies to bolster the anti-cancer therapy, but do not target cancer cells by their PD-1 expression. Instead, these chemotherapeutics work by binding to DNA in cancer cells and preventing DNA replication and transcription once they have been localized by the immunotherapeutic. Thus, the combination therapies taught in the prior are used in combination to localize the overexpression of PD-1 on cancer cells such as keratinizing nasopharyngeal carcinomas, then apply additional means to kill the cancer cells, and not a specific histology.
Applicant argues “the present application provides unexpected experimental evidence that contradicts the general expectation that keratinizing NPC would respond poorly to immunotherapy”. This is not found persuasive.
As discussed supra, the prior art references teach the same limitations as are recited in the instant claims regarding the same patient population, cancer type, and dosage regimen. It is unclear how the prior art, which teaches the limitations of the instant claims, would not obtain the same results as the instant invention. Additionally, the evidence of unexpected results must be commensurate in scope with the claimed invention (see MPEP §716.02(d)).
There is no unexpected result since the prior art already taught that the combination of treatments had similar effects and one would expect that combining them would produce a better product, as shown in Marshal. Please see MPEP 7106.0 (a), I, which states that “a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) (Evidence showing greater than additive sweetness resulting from the claimed mixture of saccharin and L-aspartyl-L-phenylalanine was not sufficient to outweigh the evidence of obviousness because the teachings of the prior art lead to a general expectation of greater than additive sweetening effects when using mixtures of synthetic sweeteners.).“ The evidence provided by Applicant of unexpected results falls into the additive sweetness combination example and does not show a greater than expected outcome and therefore, the instant invention is obvious over the combination of references.
Therefore, the rejection has been maintained in view of amendments to the claims.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 SELAM BERHANE whose telephone number is (571)272-6138. The examiner can normally be reached Monday - Friday, 9-5.
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/SELAM BERHANE/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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