DETAILED ACTION
Continued Examination Under 37 CFR 1.114
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 final rejection. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicants’ submission filed on 5/26/26 has been entered.
Status of Application, Amendments and/or Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . An RCE was filed on 6/15/26 in order to enter the after final amendment filed on 5/26/26. Claims 1 and 8 are amended. Claims 6 and 10-14 are canceled. Claims 1, 8 and 15-17 are pending.
Applicants' election without traverse of Invention I, currently all pending claims, was previously acknowledged. The elections of the following species were also previously acknowledged: (1) immune checkpoint inhibitor as the species of cancer immunotherapy agent; (2) chemical entity that blocks PD-1 as the species of immune checkpoint inhibitor; (3) pembrolizumab as the species of anti-PD-1 antibody; and (4) breast cancer as the species of cancer. The elected species read on each claim.
Claims 1, 8 and 15-17 are under consideration.
Claim Interpretation
Claim 1, as amended, in line 8 uses the term “about” in the phrase “about 25 to 300 µg/ml”. The term “about” is defined in the specification at ¶ 33 (published application) in following manner: “As used herein, the term “about” a number refers to that number plus or minus 10% of that number. The term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value”. As such, the term as used in claim 8 encompasses the recited “range minus 10% of its lowest value and plus 10% of its greatest value”, which is 22.5 to 330 µg/ml.
Withdrawn Objections and/or Rejections
The following page numbers refer to the previous Office Action (4/1/26).
The rejection of claims 1, 6 and 15-17 under 35 U.S.C. 102(a)(1) as being anticipated by Shen et al (2021) is withdrawn in view of the amendments to the claims that limit the method of independent claim 1 to embodiments not taught by Shen.
The rejection of claim 8 at pages 5-6 as being unpatentable over Shen et al (2021) as applied to claims 1 and further in view of Li et al (2021) is withdrawn in view of the amendments to the claims that limit the method of independent claim 1 to embodiments not taught by the teachings of Shen in view of Li.
New Objections
Claim Objections
Claims 1, 8 and 15-17 are objected to because of the following informalities:
In claim 1, line 4, “the nucleic acid” should be “the nucleic acid inhibitor”.
In claim 8, line 2, the comma after “Pembrolizumab,” should be removed.
In claim 8, the current amendments have deleted the period at the end of the claim. This should be restored.
The remaining claim(s) are objected to for depending from an objected claim.
Appropriate correction is required.
New rejections
Claim Rejections - 35 USC § 103
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.
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 at the time any inventions covered therein were effectively filed 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 at the time a later invention was effectively filed 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 1, 8 and 15-17 are rejected under 35 U.S.C. 103(a) as being unpatentable over Shen et al, 2021, Cell. 184: pages 352-369 and e1-10; published on-line 12/23/20 (see page 366) (cited on the 4/10/23 IDS), and further in view of the teachings of each of (1) Lam et al (2015. Molecular Therapy – Nucleic Acids. 4: 3252; pages 1-20 as printed); (2) Hattab et al (2021 Jul 2. Pharmaceutics. 13: 1009; pages 2-19 as printed); and (3) Le Louedec et al (2020. Vaccines. 8: 632; 23 pages as printed). The earliest date to which the instant application claims priority is 1/20/22.
As amended, claims 1 and 8 each encompass a method of treating cancer in an individual in need thereof by administering two individual components: (1) a nucleic acid inhibitor of FBO44 that is an FBXO44 siRNA that is administered once per week; and (2) the anti-PD-1 antibody Nivolumab, wherein the anti-PD-1 antibody achieves a plasma concentration of about 25 to 300 µg/mL.
Shen teaches that “FBXO44 expression inversely correlated with replication stress, antiviral pathways, IFN signaling, and cytotoxic T cell infiltration in human cancers, while a FBXO44-immune gene signature correlated with improved immunotherapy response in cancer patients” (see Abstract), and that “FBXO44 is associated with poor clinical outcomes in cancer patient datasets” (page 362). Shen further demonstrates successful treatment of cancer in an animal model by administering two components: “FBXO44 KD [knockdown]” and “anti-PD-1” (page 362). Shen teaches the results of this are shown in Figure 6F, which describes this as “shFBXO44 + anti-PD-1”, where shFBXO44 is a shRNA (small hairpin RNA), and anti-PD-1 is an antibody. Shen also teaches an siRNA inhibitor of FBXO44 (page 354) that can be purchased from QIAGEN (page e5). Shen concludes that FBXO44 “targeting sensitized normally refractory cancer cells to anti-PD-1 therapy” and that FBXO44 inhibitors “could have widespread application in cancer treatment, as stand-alone anti-cancer therapies and enhancers of immunotherapy response” (page 366).
Thus, Shen teaches a method of treating cancer in an individual in need thereof, comprising administering to the individual two components: (1) an shRNA nucleic acid inhibitor of F-box protein FBXO44 (i.e., shFBXO44) and (2) a cancer immunotherapy agent that is an anti-PD-1 antibody. While Shen also teaches an siRNA inhibitor of FBXO44, Shen does not expressly teach administration of this inhibitor for treatment. Shen also does not teach weekly administration of the nucleic acid inhibitor, or that the anti-PD-1 antibody is nivolumab or that administration of such achieves a plasma concentration of “about 25 to 300 µg/mL”, each as required by claim 1.
Lam et al (2015), in a review titled “siRNAs Versus miRNAs as Therapeutics for Gene Silencing”, teaches that “the therapeutic potential of siRNAs and miRNAs has been demonstrated in the treatment of many different diseases including cancers and infections” (page 1). Lam further teaches that shRNAs as an alternative means “for specific gene silencing activity in the same manner as synthetic siRNAs”, but that “[t]he requirement of viral vectors for shRNA expression poses safety concerns in therapeutic applications” (page 2).
Hattab (2021) teaches that “frequent administration of anticancer siRNAs nanotherapeutics is necessary to prevent chemotherapeutic resistance and metastasis; therefore, once to twice weekly dosing is desirable for siRNA nanotherapeutics with doses ranging up to 1.5 mg/kg” (page 10).
Le Louedec (2020), in a review titled, “Cancer Immunotherapy Dosing: A Pharmacokinetic/Pharmacodynamic Perspective”, describes “preclinical and clinical development of immune checkpoint inhibitors”, “particularly from the angle of dose finding studies” (see Abstract). In Table 1, Le Louedec sets forth the “Usual doses and clinical application of Food and Drug Administration (FDA) approved immune check-point inhibitors (ICIs)”, of which three as listed that are anti-PD-1 antibodies: Nivolumab, Pembrolizumab and Cemiplimab). Table 1 further indicates three approved dosage schedules for Nivolumab: 3 mg/kg biweekly (Q2W) or a flat dose of 200 mg every three weeks (Q3W) or 480 mg monthly (Q4W). Le Louedec further teaches that for the anti-PD-1 antibody nivolumab, “the variability in plasma nivolumab concentrations was limited” with “the variability in plasma nivolumab concentrations was limited, as shown by comparison of mean (CV%) minimum and maximum steady-state concentrations with Cmin,ss of 65.7 µg/mL (52%) vs. 55.2 µg/mL (63%) and Cmax,ss of 127 µg/mL (45%) vs. 184 µg/mL (58%) for the 480 mg Q4W and 3 mg/kg Q2W schedule, respectively” (page 6). Each of these concentrations (both minimum and maximum) falls within the anti-PD-1 antibody plasma concentration range recited in claim 1 as amended.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to take the method of treating a cancer in an individual in need thereof with a shRNA-nucleic acid inhibitor of FBXO44 and a cancer immunotherapy agent that is an anti-PD-1 antibody as taught by Shen, and modify it as follows:
Substitute siRNA as taught by Lam for the shRNA taught by Shen, motivated by the safety concerns for shRNA taught by Lam, with a reasonable expectation of success in using siRNA in view of the teachings of Lam that siRNA has been used in treatment of many diseases, including cancer;
Administer the siRNA weekly as taught by Hattab, motivated by the teachings of Shen being silent as to the regimen for administration of the FBXO44 in a human individual with cancer, with a reasonable expectation of success in treatment with such a regimen based on Hattab teaching that frequent administration of anticancer siRNA therapeutics is necessary; and
Employ Nivolumab as the anti-PD-1 antibody and administer it in a dosage taught by Le Louedec (which would result in a plasma concentration taught by Le Louedec), motivated because Shen while teaches use of anti-PD-1 antibodies in general, it does not specify a particular anti-PD-1 antibody, and Lam provides this information, with a reasonable expectation of success based on Lam teachings that such dosages are approved by the FDA for treatment of cancer.
This rationale supports a prima facie conclusion of obviousness in accord with KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (2007).
Claim 15 encompasses a method of claim 1 wherein the cancer is breast cancer. The studies of Shen utilize “4T1 breast cancer cells” (page 362), and Shen further teaches that “FBXO44 was expressed at low levels in normal breast tissues and increased with tumor stage” and “High FBXO44 expression correlated with poor patient outcome in several major cancer types” in Figure 7C, including breast cancer, indicating that the teachings of Shen are directed to treatment of breast cancer. As such, it would have further been obvious to treat cancer that is breast cancer when practicing the method of claim 1 that is obvious over the teachings of Shen in view of the teachings of Lam, Hattab and Le Louetec.
Claims 16 and 17 encompass a method of claim 1 wherein the cancer is treatment resistant (claim 16) and wherein the individual was previously treated with another cancer immunotherapy agent (claim 17). As described above, Shen teaches that FBXO44 targeting “sensitized normally refractory cancer cells to anti-PD-1 therapy” (page 366). Shen further teaches that FBXO44 inhibition as converting “‘‘cold’’ tumors, which are poorly immunogenic and non-responsive to immunotherapy, to ‘‘hot’’” (page 366). As such, Shen teaches treatment of cancer that is resistant and non-responsive to anti-PD-1 therapy alone, which is encompassed by “another cancer immunotherapy agent”. As such, it would have further been obvious to treat cancer that is resistant to treatment and previously treated with another cancer immunotherapy agent when practicing the method of claim 1 that is obvious over the teachings of Shen in view of the teachings of Lam, Hattab and Le Louetec.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY C HOWARD whose telephone number is (571)272-2877. The examiner can normally be reached on Monday to Friday from 9 AM to 5 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford, can be reached at telephone number (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center to authorized users only. Should you have questions about access to the USPTO patent electronic filing system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Examiner interviews are available via a variety of formats. See MPEP § 713.01. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/InterviewPractice.
/ZACHARY C HOWARD/Primary Examiner, Art Unit 1674
Prosecution Insights