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 .
Election/Restrictions
Applicant’s election without traverse of the species renal cell carcinoma as the cancer in the reply filed on January 26, 2026 is acknowledged.
Claims 176-198 are under consideration in this office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application claims benefit to U.S. Provisional Application Nos. 63/131,240 filed 12/28/2020, 63/150/420 filed 2/17/2021, and 63/184,082 filed 5/4/2021 and is a continuation of U.S. Application No. 17/562,958 filed December 27, 2021 and 18/423,089 filed January 25, 2024.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The new material in claims 176 and 195 that is not supported by the prior disclosures is as follows : “the total amount of nivolumab in the single unit dose and the dosing interval are sufficient for the lower limit of the two-sided 90% CI of the geometric mean ratio of at least 0.8 for average serum concentration at day 28 (Cavgd28), minimum serum concentration at day 28 (Cmind28), minimum serum concentration at steady state (Cminss), or average serum concentration at steady state (Cavgss) in the subject after the subcutaneous administration to be equal to or higher than that of an intravenous administration of nivolumab at 3 mg/kg once every two weeks… and wherein the geometric mean exposure of the subcutaneous administration is lower than the geometric mean exposure of an intravenous administration of nivolumab at 10 mg/kg once in every two weeks.” Although prior disclosures teach dosage and dosage intervals, the limitations of claims 176 and 195 regarding selection of ranges of dosage and dosage intervals based on the specific PK thresholds are not supported.
For prior art purposes, the effective filing date is the actual filing date.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on January 26, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the examiner. NPL numbers 9, 10, 25, 75, and 103 do not have a date and so have been lined through.
Claim Objections
Claim 176-178, 183 and 195 are objected to because of the following informalities:
Claims 176 use acronyms without first defining what they represent in the independent claims (i.e. “CI”). While the claims can reference acronyms, the material presented by the acronym must be clearly set forth at the first use of the acronym.
The terms Cavgd28, Cmind28, and Cavgss, as used in claims 176-178, 183, and 195, are not acronyms but applicant’s shorthand; these terms are not allowed in the claims
Appropriate correction is required.
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 176-195 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 176, 184-186, 188-189, and 195 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.
Claim 178 is dependent on itself; as such, it is unclear how to interpret the metes of bounds of what is claimed. In the interest of compact prosecution, claim 178 will be interpreted to be dependent from claim 176.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 176-189, 192, and 194-195 are rejected under 35 U.S.C. 103 as being unpatentable over US 20180044419, published February 15, 2018 (“Rosengren”; IDS from 1/26/2026, US88).
The claims are directed towards a method of treating cancer in a human subject in need thereof, comprising subcutaneously administering a pharmaceutical composition comprising about 120 mg/ml nivolumab and about 2,000 units/ml of a hyaluronidase at a dosing interval.
Rosengren teaches a method of using pharmaceutical compositions of co-formulations of a hyaluronidase and an immune checkpoint inhibitor (abstract, [0572], [0574]) in a subject with cancer [0003], as in instant claims 176 and 195. An exemplary immune checkpoint inhibitor is nivolumab [0022], as in claims 176 and 195. The compositions of Rosengren are formulated for subcutaneous delivery [0572], as in claims 176 and 195. The anti-hyaluron agent and immune-checkpoint inhibitor can be administered simultaneously [0796], as in instant claims 176 and 195.
Rosengren teaches that the checkpoint inhibitor can be between 0.5 mg/ml to 500 mg/ml, as in claims 176 and 195. Rosengren teaches that the checkpoint inhibitor is formulated between 7.5 mg to 5,000 mg [0622], as in claims 184-186
Infusion time of Rosengren can be 1 or 5 minutes [0614], as in the subcutaneous infusion time of about 3 minutes to about 5 minutes of instant claim 188.
Regarding instant claim 189m Rosengren teaches that the body weight of the subject is, on average, about 70-75 kg [0289].
Rosengren teaches that the hyaluronidae may be a soluble recombinant huma PH20 of SEQ ID NO: 123 [0200], which is identical to SEQ ID NO: 5 of instant claim 195.
Rosengren teaches that the combination therapy of anti-hyaluron agent and immune-checkpoint inhibitor can be used in further combination with other therapies or treatments, including chemotherapy [0807], as in instant claim 191. The chemotherapy of Rosengren comprises cisplatin [0829], as in the platinum-based chemotherapy of instant claims 192 and 194, and fluorouracil, as in the fluoropyrimidine-containing chemotherapy limitation of 194.
Although Rosengren teaches all the individual limitations of the claim, this reference does not explicitly set forth a pharmaceutical composition of nivolumab and a hyaluronidase. However, it would have been obvious to the ordinary artisan prior to the effective filing date of the claimed invention to arrive at the claimed pharmaceutical formulation of nivolumab and a hyaluronidase that is administered together subcutaneously with the desired effects. One of ordinary skill in the art would have been able to generate this preferred therapeutic dosing protocol via routine optimization of the method of Rosengren and have a reasonable and predictable expectation of success (see MPEP § 2144.05). This is because the artisan has good reason to pursue known options within their technical grasp to obtain predictable results.
Rosengren teaches pharmaceutical compositions comprised of immune checkpoint inhibitor/nivolumab and hyaluronidase at the claimed concentrations. “(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, 220F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.III.A, which states that applicants can rebut a prima facie case of obviousness by showing the criticality of the range. "The law is replete with cases in which the difference between the claimed invention and the prior art is some range or other variable within the claims. . . . In such a situation, the applicant must show that the particular range is critical, generally by showing that the claimed range achieves unexpected results relative to the prior art range." In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Thus, the burden is on the applicant to demonstrate that the method of treating cancer comprised of a combination of nivolumab and a hyaluronidase at the doses and dosing intervals is directed to unexpected results. Types of unexpected results include greater than expected results, superiority of a property shared with the prior art, presence of an unexpected property, or absence of an expected property (see MPEP 716.02(a)I. There is no evidence that administering a formulation of 120 mg/ml nivolumab and 2,000 units/ml hyaluronidase, within the limitations described, is critical compared to the regimen taught by Rosengren.
Limitations of claims 176-183, 187, and 195 directed to the total amount of nivolumab and the dosing interval sufficient “to lower limit of the two-sided 90% CI of the geometric mean ratio of at least 0.8 for average serum concentration at day 28 (Cavgd28), minimum serum concentration at day 28 (Cmind28), minimum serum concentration at steady state (Cminss), or average serum concentration at steady state (Cavgss) in the subject after the subcutaneous administration to be equal to or higher than that of an intravenous administration of nivolumab at 3 mg/kg once every two weeks… and wherein the geometric mean exposure of the subcutaneous administration is lower than the geometric mean exposure of an intravenous administration of nivolumab at 10 mg/kg once in every two weeks” are drawn to metrics demonstrating noninferiority of the claimed method over intravenously administered composition comprising nivolumab and hyaluronidase. While Rosengren is silent regarding the noninferiority of subcutaneous administration over intravenous administration, it is clear that the pharmaceutical composition of Rosengren comprising 120 mg/ml nivolumab and 2,000 units/ml hyaluronidase when administered to a subject with cancer would have the same characteristics as the instantly claimed subcutaneous unit dosage form, since there is no evidence to the contrary. Further, since the subcutaneous unit dosage form of Rosengren satisfies all the structural limitations set forth in the claims, it necessarily follows that the claimed unit dosage form inherently possesses the functionality and the ability to serve the intended use recited in the claims, e.g., the treatment of cancer. One looking to treat cancer in a subject by administering subcutaneously the composition comprising nivolumab and a hyaluronidase would attempt to identify via methods known in the pharmaceutical art doses that would
When the references disclose all the limitations of a claim except a property or function, and the examiner cannot determine whether or not the reference inherently possesses properties which anticipate or render obvious the claimed invention, the burden shifts to the applicant, as in In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980), See MPEP 2112-2112.02. In the instant case, Rosengren teaches the antibody, the dose, and the administration step for treating a subject with cancer. In the absence of any unexpected results regarding the method, the instant claims are obvious over the teachings of Rosengren.
Claims 176-190, 192, and 194-195 are rejected under 35 U.S.C. 103 as being unpatentable over US 20180044419 (“Rosengren”) in view of Motzer et al, published November 5, 2015 (IDS from 1/26/2026, NPL46).
The teachings of Rosengren are discussed above; Rosengren does not teach a method for treating renal cell carcinoma, as required by 190.
Motzer teaches that patients with advanced renal-cell carcinoma who were treated with nivolumab exhibited longer overall survival (see abstract). Thus, it would have been obvious to the ordinary artisan to apply the method of Rosengren in patients with advanced renal-cell carcinoma, because this patient population has been shown to be responsive to nivolumab therapy.
Claims 176-189, and 192-195 are rejected under 35 U.S.C. 103 as being unpatentable over US 20180044419 (“Rosengren”) in view of Bergerot et al, published December 2, 2019 (IDS from 1/26/2026, NPL136).
Rosengren does not teach a method for cancer comprising the chemotherapy cabozantinib, as
required by claim 193.
Bergerot et al teaches a method for treating metastatic renal cell carcinoma comprising nivolumab in combination with cabozantinib; preliminary clinical results indicate tolerability and efficacy
(pg 2190; column 1). Thus, it would have been obvious to the ordinary artisan to add cabozantinib to
the method of Rosengren and have a reasonable expectation of success, because the benefits of the
combination therapy were already taught by Bergerot et al.
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 176-195 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 174 and 192-220 of copending Application No. 18/423,089. Although the claims at issue are not identical, they are not patentably distinct from each other because they are directed to overlapping embodiments: a method of treating cancer comprised of administering a composition comprising 120 mg/ml nivolumab and a hyaluronidase. The hyaluronidase in each application is comprised of SEQ ID NO: 5.
While the claims of ‘089 are silent on the intended results of instant claims 178-183, 187, and 194, it is clear that the same formulation of nivolumab in a method of treating cancer would have the same characteristics as the instantly claimed composition since there is no evidence to the contrary. Note that rejections for obviousness are appropriate when the prior art discloses a method (or product) that appears to be identical except that the art is silent as to an inherent property; see MPEP § 2112(III). In such situations, the burden is on applicant to provide evidence that the prior art product (or method) is not obviously the same.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 176-195 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 51, 58, 62, 64, 75-81, and 168-182 of copending Application No. 18/812,813. Although the claims at issue are not identical, they are not patentably distinct from each other because they are directed to overlapping embodiments: a method of treating cancer comprised of administering a composition comprising 120 mg/ml nivolumab and a hyaluronidase.
The claims of application ‘813 teach a pharmaceutical composition comprising nivolumab and a hyaluronidase as well as a method of treating cancer comprising administering the composition. The hyaluronidase in each application is comprised of SEQ ID NO: 5.
While the claims of ‘813 are silent on the intended results of instant claims 178-183, 187, and 194, it is clear that the same formulation of nivolumab in a method of treating cancer would have the same characteristics as the instantly claimed composition since there is no evidence to the contrary. Note that rejections for obviousness are appropriate when the prior art discloses a method (or product) that appears to be identical except that the art is silent as to an inherent property; see MPEP § 2112(III). In such situations, the burden is on applicant to provide evidence that the prior art product (or method) is not obviously the same.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 176-195 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 176-215 of copending Application No. 18/736,323. Although the claims at issue are not identical, they are not patentably distinct from each other because they are directed to overlapping embodiments: a method of treating cancer comprised of administering a composition comprising 120 mg/ml nivolumab and a 2,000 units/ml hyaluronidase. The hyaluronidase in each application is comprised of SEQ ID NO: 5. Further, the single unit dose and dosing interval of the ‘323 claims are the same as those of in the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 176-195 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 176-195 of copending Application No. 19,343,935 in view of Motzer et al, published November 5, 2015. Although the claims at issue are not identical, they are not patentably distinct from each other because they are directed to overlapping embodiments: a pharmaceutical composition comprising 120 mg/ml nivolumab a hyaluronidase. The hyaluronidase in each application is comprised of SEQ ID NO: 5.
The claims of application ‘181 teach a method of administering the same pharmaceutical composition of the instant claims; as such, the compositions are not patentably distinct from each other. The claims of ‘935 do not teach a method of treating cancer, as required by independent claims 176 and 195.
Motzer teaches that patients with advanced renal-cell carcinoma who were treated with nivolumab exhibited longer overall survival (see abstract). Thus, it would have been obvious to the ordinary artisan to apply the method of Rosengren in patients with cancer, including advanced renal-cell carcinoma, because this patient population is responsive to nivolumab therapy.
While the claims of ‘935 in view of Motzer are silent on the intended results of instant claims 178-183, 187, and 194, it is clear that the same formulation of nivolumab in a method of treating cancer would have the same characteristics as the instantly claimed composition since there is no evidence to the contrary. Note that rejections for obviousness are appropriate when the prior art discloses a method (or product) that appears to be identical except that the art is silent as to an inherent property; see MPEP § 2112(III). In such situations, the burden is on applicant to provide evidence that the prior art product (or method) is not obviously the same.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER BENAVIDES whose telephone number is (571)272-0545. The examiner can normally be reached M-F 9AM-5PM (EST).
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Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/Examiner, Art Unit 1675