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 .
Claim Status
Claim listing filed on February 23, 2026 is pending. Claims 1, 3, and 7 are amended. Claims 14-24 are new. Claims 2, 4-5, and 8-13 are canceled. Claims 1, 3, 6-7, and 14-24 are examined upon their merits.
Withdrawn Objections and Rejections
Applicant’s cancelation of Claims 2, 4-5, and 11-13 have rendered all previous rejections directed to these claims moot.
The amendments to the specification overcome the objection of record, and the specification objection is withdrawn.
The rejection of Claims 1, 3, and 6-7 under 35 U.S.C. 112(b) as being indefinite is withdrawn in view of Applicant’s amendments. In particular, Claim 1 defines wherein the proto-oncogene product targeting inhibitor is bevacizumab which provides proper structure and overcomes the indefinite functional language.
The rejection of Claims 1, 3, and 6-7 under 35 U.S.C. 112(a) as failing to comply with the written description and enablement requirements is withdrawn in view of Applicant’s amendments. In particular, Claim 1 defines wherein the proto-oncogene product targeting inhibitor is bevacizumab and wherein the PEG-interferon is a PEG-interferon α1b. Therefore, the claims are no longer directed to a genus of inhibitors and a genus of PEG-interferons.
The rejection of Claims 1 and 6-7 under 35 U.S.C. 102(a)(1) as being anticipated by Hoffmann-La Roche NCT02174172 (2014) is withdrawn in view of Applicant’s amendments. In particular, Hoffmann fails to teach wherein the PEG-interferon is a PEG-interferon α1b as required by amended Claim 1.
The rejection of Claims 1, 3, and 6-7 under 35 U.S.C. 103 as being unpatentable over Hoffmann-La Roche NCT02174172 (2014) in view of Masci et al. Clin Pharmacol Ther. 2007 and Wu CN1634993A published 2005 is withdrawn in view of Applicant’s amendments. Hoffmann in view of Masci and Wu fail to teach wherein the renal carcinoma is human renal carcinoma 786-O as required by amended Claim 1.
The provisional rejection of Claims 1, 3, 6-7 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3, 6-7, and 11 of copending U.S. App. No. 17/754,351 in view of Hoffmann-La Roche NCT02174172 2014 and Masci et al. Clin Pharmacol Ther. 2007 is withdrawn in view of Applicant’s amendments. The copending claims in view of Hoffmann and Masci fail to teach wherein the renal carcinoma is human renal carcinoma 786-O as required by amended Claim 1.
Claim Rejections - 35 USC § 103 (Modified, necessitated by amendment)
The rejection of Claims 1, 3, 6-7, and 14-24 under 35 U.S.C. 103 as being unpatentable over Hoffmann-La Roche NCT02174172 2014 (of record) in view of Masci et al. Clin Pharmacol Ther. 2007 (of record) and Wu CN1634993A 2005 (of record), and further in view of Brodaczewska et al. Molecular Cancer 2016 (of record) is maintained. The rejection of record applied to Claims 1, 3, and 6-7 and now applies to Claims 1, 3, 6-7, and 14-24 due to Applicant’s amendments.
It is of record in the non-final office action filed 11/21/2025 that Hoffmann teaches a Phase 1 interventional clinical trial wherein patients with advanced or metastatic renal cell carcinoma are treated with bevacizumab, PEG-interferon α2a, and atezolizumab (Arm D, brief summary). Atezolizumab and bevacizumab are administered by IV infusion and PEG-interferon α2a is administered by subcutaneous injection (Arm D, Study Plan) which anticipates formulating the active ingredients as pharmaceutical compositions comprising pharmaceutically acceptable carriers. Note, atezolizumab is an antitumor agent which reads on Claim 24. Hoffmann further teaches wherein the bevacizumab is administered at 15 mg/kg every 3 weeks and PEG-interferon α2a is administered at 180 µg every 3 weeks (Arm D, Study Plan).
Hoffmann fails to teach wherein the PEG-interferon is a PEG-interferon α1b (Claim 1). Masci teaches that five renal cell carcinoma patients treated with IFN-α1b had progression-free survival for more than one year, and Masci summarizes that IFN-α1b resulted in potent stimulation of IFN-regulated genes and tumor regressions in renal cell carcinoma (abstract). The acute toxicities of IFN-α1b were quantitatively less than those expected from IFN-α2 (discussion paragraph 1). Specifically, the chronic side effects of fatigue, weight loss, and altered mood that are troublesome with IFN-α2 treatment were relatively infrequent with IFN-α1b treatment and were clinically manageable (discussion paragraph 6). Masci teaches that the doses of IFN-α1b were escalated from 15 µg/m2 to 270 µg/m2 (Table 2) which is approximately equivalent to 0.4 µg/kg to 7.3 µg/kg. Wu teaches that IFN-α1b has a relatively short in vivo half-life (paragraph [0004]), and formulating IFN-α1b as mPEG-IFN-α1b has an advantageous longer in vivo half-life (paragraph [0006]) while maintaining biological activity (paragraphs [0063]-[0066]).
The dosages taught by Hoffmann and Masci read on Claims 1, 3, and 14-22 because dosages and dosage ratios are results-effective variables which can be optimized. In the case of administering PEG-interferon α1b and bevacizumab, one of skill in the art would clearly recognize that the relative doses must be sufficient to maintain the efficacy of the drugs in vivo and could easily be optimized by a treating physician based on the needs and physiology of an individual patient. Frequency of administration (i.e. treatment schedule) and method of administration (i.e. intravenous or subcutaneous) are further results-effective variables that affect effective drug concentration in a subject. As such, the dosages would amount to nothing more than routine experimentation that can be optimized on an individual patient basis (see In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977); and In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980)). " Further, in In re Aller, 220 F. 2d454, 456, 105 USPQ 233,235 (CCPA 1955) the courts maintained that: "Where the general condition of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." As dosage optimization is routine in the art of medicine and pharmacology, Claims 1, 3, and 14-22 are considered to be prima facie obvious over the teachings of Hoffmann and Masci.
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to adapt the method of treating renal cancer by administering bevacizumab and PEG-IFN-α2a taught by Hoffmann by substituting the PEG-IFN-α2a for PEG-IFN-α1b as taught by Masci and Wu. Masci teaches that IFN-α1b effectively treats patients with renal cancer. The motivation to administer IFN-α1b instead of IFN-α2a is because IFN-α1b showed less frequent toxic side effects than is expected from IFN-α2 (Masci discussion). Further, it is obvious to formulate the IFN-α1b as PEG-IFN-α1b to favorably increase the in vivo half-life (Wu paragraph [0006]). One of ordinary skill in the art could have substituted PEG-IFN-α2a for PEG-IFN-α1b with a reasonable expectation of success in treating renal carcinoma.
Hoffmann in view of Masci and Wu fail to teach wherein the renal carcinoma is human renal carcinoma 786-O (Claim 1). Brodaczewska teaches that 786-O is one of the first established renal cell carcinoma (RCC) cell lines (page 5, paragraph 2). 786-O has many characteristics of clear cell RCC (ccRCC) and is used most commonly in RCC-focused research (page 5, paragraph 2). The 786-O cell line can be injected into mice to study RCC in vivo (page 5, paragraph 2).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to adapt the method of treating renal cancer by administering bevacizumab and PEG-IFN-α1b as taught by Hoffmann, Masci, and Wu to specifically treat human renal carcinoma 786-O as taught by Brodaczewska. Brodaczewska teaches that 786-O is a cell line most commonly used in RCC-focused research. Therefore, it would be obvious to administer the drug combination in models of 786-O RCC because the cell line is a standard in the field.
Applicant's arguments filed February 23, 2026 have been fully considered but they are not persuasive. Applicant argues that the synergistic effect of PEG-interferon α1b in combination with bevacizumab against human renal carcinoma 786-O is not an inherent property of the methodological step of administering as stated by Examiner in the non-final office action filed 11/21/2025 (page 5). Applicant supports that the synergistic effect is not an inherent property because no such synergistic effect was observed against human renal carcinoma Caki-1 (specification Example 1); therefore, the synergistic effect of PEG-interferon α1b and bevacizumab is not universal across all renal cancer cell lines but is instead specific to human renal carcinoma 786-O. This argument is not persuasive because the specification clearly states that the combination of PEG-interferon α1b and bevacizumab does have a synergistic effect in human renal carcinoma Caki-1 (“PEG-interferon α1b had a synergistic effect on subcutaneous transplanted tumors of human renal carcinoma Caki-1 in nude mice treating with Avastin, wherein PEG-interferon α1b in medium dose of 1 mg/kg had a significant enhancement effect on Avastin (P < 0.05, compared with PEG-interferon α1b or Avastin monotherapy), showing a synergistic effect” (paragraph spanning pages 21-22)). This section of the specification implies that a synergistic effect is present because the combination is significantly more effective than either monotherapy. Applicant’s remarks define a synergistic effect by a different metric wherein synergy is present when the combination effect is greater than the sum of the two monotherapy effects (remarks pages 10 and 12). The specification provides no definition of “synergistic” or “synergy” and teaches no methods of quantifying drug interactions. The state of the art prior to filing teaches that there are multiple ways to quantify drug combination synergy that each have advantages and disadvantages (as evidenced by Ma et al. Proteom Bioinform. July 2019). Therefore, the broadest reasonable interpretation of “synergistic” is that the synergistic effect can be quantified by any method known in the art prior to filing. Thus, the instant specification that teaches a synergistic effect in Caki-1 because the combination is significantly more effective than either monotherapy is accepted by the Examiner as “synergistic treatment.” Both renal cancer cell lines (Caki-1 and 786-O) and a liver cancer cell line (Huh-7) tested in the specification showed a synergistic effect when administering PEG-interferon α1b and bevacizumab. Examiner maintains the interpretation of record that a synergistic effect is an inherent property of the methodological step of administering PEG-interferon α1b and bevacizumab (MPEP § 2112.01-.02), because the disclosure teaches nothing to the contrary.
Further, the state of the art prior to filing supports this interpretation by teaching that bevacizumab and IFN may have synergistic effects when combined because both agents have stimulatory effects on the immune response (Melichar et al. Annals of Oncology 2008; page 1471). Specifically, bevacizumab and IFN treatment are both understood to improve the function of dendritic cells which is suppressed in advanced cancer (Melichar page 1471). In addition to the mechanistic rationale, Melichar teaches preclinical evidence that the drugs are synergistic because the antiangiogenic and immunotherapeutic effects of bevacizumab and low-dose IFN are more pronounced when used in combination (Melichar page 1475). The teachings of Melichar are cited not as a new ground of rejection but solely in response to Applicant’s arguments to support that a synergistic effect is an inherent property of administering PEG-interferon α1b and bevacizumab based on their mechanisms of action. The state of the art prior to filing supports the Examiner’s interpretation of the inherent property of the drug combination, and nothing in the disclosure contradicts this interpretation as the combination displayed synergy in all three cell lines tested (Examples 1-3).
Applicant argues that the synergistic effect in human renal carcinoma 786-O is unexpected over the prior art. Examiner maintains that the ability of PEG-interferon α1b and bevacizumab to effectively treat renal carcinoma is obvious over Hoffmann, Masci, and Wu as described above, and the claimed synergistic effect is an inherent property of administering the drug combination. One of ordinary skill would expect the two drugs to work well in combination in effectively treating renal carcinoma. Just because a high synergistic effect was observed in the 786-O cell line does not make the results unexpected, because the results are a matter of degree and not a matter of kind. See UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 693, 2023 USPQ2d 448 (Fed. Cir. 2023): "A difference of degree is not as persuasive as a difference in kind – i.e., if the range produces ‘"a new property dissimilar to the known property,’" rather than producing a predictable result but to an unexpected extent." (MPEP § 716.02). Therefore, a difference in degree of synergy in the 786-O cell line does not negate the fact that one of ordinary skill would have predicted the combination to effectively treat renal cancer with a reasonable expectation of success. An example of an unexpected result in view of the prior art would be if the combination showed tumor promoting effects (i.e. a difference in kind of effect, not a difference in degree of effect). Applicant’s arguments have been considered, but they are not persuasive and the rejection is maintained.
Double Patenting (New, necessitated by amendment)
1. Claims 1, 3, 6-7, and 14-24 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 3-4, 7, 14-17, and 19 of copending U.S. App. No. 17/754,351 in view of Hoffmann-La Roche NCT02174172 2014 (of record), Masci et al. Clin Pharmacol Ther. 2007 (of record), and Brodaczewska et al. Molecular Cancer 2016 (of record).
The instant claims are directed to a method for synergistic treatment of renal carcinoma by administering a PEG-interferon α1b at a dose of 50 ng/kg body weight to 10 mg/kg body weight and bevacizumab at a dose of 50 ng/kg body weight to 10 mg/kg body weight wherein the renal carcinoma is human renal carcinoma 786-O (Claims 1 and 20-22). Dependent claims recite: a mass ratio of the PEG-interferon α1b to bevacizumab is 1:100 to 500:1 (Claims 3 and 14-16) or a ratio of 1,000 IU/mg to 100 million IU/mg (Claims 3 and 17-19); a pharmaceutical composition comprising the active ingredients (Claim 6); wherein the pharmaceutical composition further comprises an additional antitumor agent (Claims 7 and 24); and wherein the PEG-interferon α1b is administered before, during, or after administration of bevacizumab (Claim 23).
The copending claims recite a method for treatment of a tumor by administering PEG-interferon α1b at a dose of 50 ng/kg body weight to 10 mg/kg body weight and bevacizumab at a dose of 50 ng/kg body weight to 10 mg/kg body weight wherein the PEG-interferon α1b is administered before, during, or after the bevacizumab (Claims 1, 16-17, and 19). Dependent claims recite: a mass ratio of the PEG-interferon α1b to bevacizumab is 1:100 to 500:1 (Claim 3) or a ratio of 1,000 IU/mg to 100 million IU/mg (Claims 3 and 14-15); wherein the tumor is a cancer tumor (Claim 4); and a pharmaceutical composition comprising the active ingredients and a pharmaceutically acceptable carrier (Claim 7).
The copending claims teach the treatment of a cancerous tumor but do not teach wherein the tumor is specifically human renal carcinoma 786-O (instant Claim 1) or wherein the pharmaceutical composition further comprises an antitumor agent (instant Claims 7 and 24).
Hoffmann teaches a Phase 1 interventional clinical trial wherein patients with advanced or metastatic renal cell carcinoma are treated with bevacizumab, PEG-interferon α2a, and atezolizumab (Arm D, brief summary). Masci teaches that five renal cell carcinoma patients treated with IFN-α1b had progression-free survival for more than one year, and Masci summarizes that IFN-α1b resulted in potent stimulation of IFN-regulated genes and tumor regressions in renal cell carcinoma (abstract). Brodaczewska teaches that 786-O is one of the first established renal cell carcinoma (RCC) cell lines (page 5, paragraph 2). 786-O has many characteristics of clear cell RCC (ccRCC) and is used most commonly in RCC-focused research (page 5, paragraph 2).
Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating a cancerous tumor as outlined in the copending claims to specifically treat human renal carcinoma 786-O as taught by Hoffmann, Masci, and Brodaczewska. Hoffmann and Masci teach that bevacizumab, PEG-interferon α2a, and IFN-α1b are all known to have antitumor efficacy in renal cancer. Brodaczewska teaches that 786-O is a standard renal carcinoma cell line used in the field. Further, Hoffmann teaches further administering the antitumor agent atezolizumab. It would have been obvious to apply the known method of cancer treatment to the renal carcinoma disease setting because Hoffmann teaches that bevacizumab and PEG-IFN-α2a can be administered to treat renal carcinoma and Masci teaches that IFN-α1b can be administered to treat renal carcinoma. The motivation to apply the treatment specifically to models of 786-O is because it is an established cell line that is a standard in the renal carcinoma field. One of ordinary skill could apply the known treatment method to the renal carcinoma disease setting with a reasonable expectation of success. Thus, the method of the instant claims is either anticipated and/or rendered obvious by the copending claims in view of Hoffmann, Masci, and Brodaczewska.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Note, Applicant's remarks filed February 23, 2026 fail to argue why the provisional nonstatutory double patenting rejection is improper. Thus, the rejection has been appropriately applied to the amended claims.
Conclusion
No claim is allowed.
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.
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/SARAH COOPER PATTERSON/ Examiner, Art Unit 1675
/JEFFREY STUCKER/ Supervisory Patent Examiner, Art Unit 1675
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