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/Restriction
Applicant’s election of species without traverse in the reply filed on 06/04/2026 is acknowledged.
Applicant has elected:
A combination of chemotherapy and immunotherapy
An interferon or mutant or derivative thereof
Type I interferon
Interferon alpha 2b
Pegberon
STINGs
MK-1454
H)(a)(i) Gemcitabine
I) Liver cancer
Upon reevaluation for the restriction of group D, “mutant or derivative thereof” has been rejoined with the elected species of interferon alpha 2b for prosecution.
Furthermore, in H(a)(i) cisplatin has been joined with Gemcitabine for prosecution.
Claim Status
Claims 1-35 are pending. No claims have been withdrawn or canceled. Claims 1-35 are herein examined.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement filed 01/25/2024 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. It has been placed in the application file, but the information referred to therein has not been considered.
Furthermore, the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper."
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 6, 8, 10, 11, 14-19, 16, 21, 22, 24, 27, 29, 31, 32, and 35 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.
Claim 6 is rejected as indefinite for recitation of exemplary language “e.g.” followed by narrower limitation “no visible lesion (tumor)”. It is unclear if what follows “e.g.” is an exemplary embodiment of complete remission or a limitation. Furthermore, reciting an exemplary indication of a visible lesion, “tumor” in parenthesis, is indefinite. Because it is unclear what the art must teach in order to infringe on the claim, the metes and bounds of the claim unclear. For the purposes of examination “e.g. no visible lesion (tumor)” will be treated as exemplary and therefore not required by the claim.
Claim 8 is rejected as indefinite because it lacks antecedent basis for “the interferon”. For the purposes of examination, “the interferon” will be interpreted as “the interferon-based therapeutic agent”; Claim 8 will still be interpreted as dependent from claim 1.
Claim 10 is rejected as indefinite because it lacks antecedent basis for “the interferon or the mutant or derivative thereof”. For the purposes of examination, claim 10 will be interpreted as dependent from claim 7, which recites “an interferon or the mutant or derivative thereof”.
Claims 11 and 32 contain the trademark/trade name Pegberon. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a type of interferon alpha 2b and, accordingly, the identification/description is indefinite. For the purposes of examination, “Pegberon” will simply be interpreted as “a pegylated interferon alpha 2b”.
Claim 14 is rejected as indefinite for recitation that the concentration of neopterin must be higher in the subject relative to the concentration prior to the first administration of an interferon followed by the exemplary term “for example” followed by species of relative neopterin concentrations “approximately 110%, approximately 120%... or higher…”. As recited, it is unclear if the species are required by the claim. Therefore, it is unclear if art that reads on the genus but not the species, such as a relative neopterin concentration post-administration of 101%, would read on the claim. Therefore, the metes and bounds of the claim are unclear.
Claims 14-19 are rejected as indefinite because they lack antecedent basis for “the consecutive treatment course”. For the purposes of examination, “the consecutive treatment course” will be interpreted as “the consecutive course” and Claims 14-19 will be interpreted as dependent from claim 2, which recites “at least one consecutive course”. For the purposes of examination, the definition of “consecutive course” will be the same as “consecutive treatment course” used in the specification (pg. 9, second paragraph).
Claim 15 is rejected as indefinite for reciting “plus about 5 in vivo half-lives of the therapeutic agent” because it renders the metes and bounds of the claimed duration unclear. It is unclear whether the limitation defines the endpoint of the duration by requiring a period of 5 half-lives after the last administration or whether the limitation defines the period between the first and last administration by requiring the first and last administrations to be about five in vivo half-lives apart. For the purposes of interpretation, the duration will interpreted as the period from the first administration until the time it takes on average for 5 in vivo half-lives of the therapeutic agent to occur after the last administration.
Claims 16 and 17 are rejected as indefinite because it lists embodiments that are “preferably”, “further preferably”, and “yet further preferably” selected. It is not clear whether the recitation of “preferably”, “further preferably”, and “yet further preferably” embodiments are preferred examples- and therefore not limiting- or are further limitations of the scope of the claim. Therefore, the metes and bounds of the claim are unclear. For the purposes of examination, “preferably”, “further preferably”, and “yet further preferably” will be interpreted as examples that are not required by the claims.
Claim 21 is rejected as indefinite because it lacks antecedent basis for “the durations of the plurality of consecutive treatment courses”. For the purposes of examination, “the durations of the plurality of consecutive treatment courses” will be interpreted as “the durations of the plurality of consecutive courses” and Claim 21 will be interpreted as dependent from claim 3, which recites “a plurality of consecutive courses”.
Claim 22 is rejected as indefinite because it lacks antecedent basis for “the intervals between the consecutive treatment courses”. For the purposes of examinations, “the intervals between the consecutive treatment courses” will be interpreted as “the intervals between the consecutive courses” and claim 22 will be interpreted as dependent from claim 3.
Claims 24 and 35 are rejected as indefinite for reciting a genus “a chemotherapeutic agent” follow by an exemplary language special term “such as” followed by the species Gemcitabine. It is unclear if the art is required to teach the genus or just the species in order to meet the claim limitation. Therefore, the metes and bounds of the claim are unclear.
Claim 27 is rejected as indefinite because it lacks antecedent basis for “the method”. For the purposes of claim interpretation, it will be interpreted as “…which is used for treating cancer recurrences in a subject.”
Claim 29 is rejected as indefinite because it lacks antecedent basis for “the interferon”. For the purposes of claim interpretation, “the interferon” will be interpreted as “the interferon-based therapeutic agent”. Claim 29 will still be interpreted as dependent from claim 26.
Claim 29 is also rejected as indefinite for recitation of exemplary language “such as” and “preferably” followed by narrower limitation “interferon [Symbol font/0x61], interferon [Symbol font/0x62], interferon [Symbol font/0x67] or interferon [Symbol font/0x6C]”, and “interferon [Symbol font/0x61]” respectively. It is unclear if what follows “such as” and “preferably” is an exemplary embodiment that is required by the claims. Because it is unclear what the art must teach in order to infringe on the claim, the metes and bounds of the claim unclear. For the purposes of examination limitations following follows “such as” and “preferably” will be treated as exemplary and therefore not required by the claim. Claim 31 is rejected as indefinite because it lacks antecedent basis for “the interferon or the mutant or derivative thereof is PEGylated”. For the purposes of examination, it will be interpreted as dependent from claim 28, which recites “an interferon or a mutant or derivative thereof”.
Claim Rejections - 35 USC § 112(a)
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 1-25 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for delaying and reducing cancer recurrence, does not reasonably provide enablement for preventing cancer recurrence. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The breadth of the claims:
Claims 1-25 recite a method of preventing cancer recurrence in a subject comprising administering an interferon-based therapeutic agent, and optionally administering an additional anticancer agent to the subject.
Under broadest reasonable interpretation, preventing cancer recurrence means permanently preventing cancer from recurring, curing the subject.
Accordingly, the specification and state of the art provide enablement for delaying and reducing cancer recurrence in a subject comprising administering an interferon-based therapeutic agent, and optionally administering an additional anticancer agent to the subject.
The state of the art and nature of the claimed invention:
The state of the art teaches that surgery is used to remove tumors from subjects, but that cancer recurrence from this technique is common due to residual microtumors and circulating tumor cells (Lu, Engineered PLGA microparticles for long-term, pulsatile release of STING agonist for cancer immunotherapy, Cancer, 2020; pg. 8, left side, third paragraph; see instant PTO-892).
Interferon treatment was been studied as a therapeutic approach used to delay various types of cancer recurrence, often post-surgery, using a plethora of approaches and therapeutic treatments. For example, Ikeda (Interferon Beta Prevents Recurrence of Hepatocellular Carcinoma After Complete Resection or Ablation of the Primary Tumor—A Prospective Randomized Study of Hepatitis C Virus–Related Liver Cancer, 2000, Hepatology, pgs. 228-232; see instant PTO-892) teaches that patients with hepatitis C virus related liver cancer receiving interferon-beta treatment twice a week had significantly lower cancer recurrence in comparison to controls (Fig. 1; pg. 230, left side, third paragraph).
Lu further teaches that in a surgical resection melanoma model, mice treated with engineering polylactic-co-glycolic acid (PLGA) microparticles containing STING agonists remained tumor free sixty days (Fig. 6B).
These sources demonstrate the efficacy of interferon-based therapeutic treatment for reducing and delaying cancer recurrence. However, the state of the art is not enabling for the full breadth of “preventing cancer recurrence” because these sources teach that subjects do not remain cancer free forever. For example, Ikeda teaches an individual in the experimental group (i.e. receiving IFN-beta twice a week) did have cancer recurrence around the 2.5 year mark (Fig. 1) and Lu teaches that 2 of eight mice in the experimental group ultimately experienced cancer recurrence (pg. 3, left side, middle of second paragraph).
Furthermore, for therapeutic dosing regimens that require repeated injections, sometimes multiple times a week, Lu teaches that patient compliance is diminished which can affect treatment efficacy (pg. 1, right side, last paragraph). Patient compliance is of particular concern for interferon treatment, which as demonstrated by Ikeda, is typically administered at high frequency.
Altogether the teachings in the non-patent literature of “preventing cancer recurrence” provide enablement for delaying and reducing cancer recurrence by administering an interferon-based therapeutic but not for the full scope of preventing cancer recurrence, which includes permanent prevention.
The existence of working examples and amount of direction provided by the inventor:
The specification teaches two working examples directed toward prevention of liver and colorectal cancer recurrence by administration of PEG-mIFN-alpha 4 and/or gemcitabine (Example 4, pg. 18; Example 5, pg. 20). Figures 8 and 10 demonstrate tumor incidence in mice treated with PEG-mIFN-alpha4 and/or gemcitabine over a period of time.
For colorectal cancer, administering PEG-mIFN-alpha4 alone without an additional anticancer agent resulted in 95% tumor recurrence within 20 days of tumor inoculation, which teaches away from the efficacy of claimed invention (Fig. 10).
Tumor recurrence for mice treated with both PEG-mIFN-alpha4 and gemcitabine for liver or colorectal cancer, while greatly diminished compared to controls and other experimental groups, was not entirely prevented during the experimental period for either cancer type: the experimental group for treating liver cancer experienced cancer recurrence from roughly days 30-70 (Fig. 8) and the experimental group for treating colorectal cancer plateaued around 45% tumor recurrence starting around day 65 (Fig. 10).
Furthermore, even for the periods of time at which the data demonstrate that the subjects treated with PEG-mIFN-alpha4 and gemcitabine have 0% cancer recurrence, it does not necessarily mean that cancer was entirely prevented during this period of time because the specification (pg. 19, paragraph 4) teaches that tumor recurrence was only counted once the tumor was greater than or equal to 62.5mm3.
Thus, the working examples in the specification teach that while cancer recurrence can be greatly diminished and even delayed for a period of time using a combination of PEG-mIFN-alpha4 and gemcitabine, they do not demonstrate that cancer recurrence is entirely or permanently prevented, especially when subjects are treated with PEG-mIFN-alpha4 alone.
Quantity of experimentation need to use the invention:
Based on the content of the disclosure and the teachings from the state of the art, a significant amount of experimentation would be required to use the claimed invention, if it is even possible.
Conclusion:
Altogether, the state of the art and detail within the disclosure provide enablement for delaying and reducing cancer recurrence by administering an interferon-based therapeutic agent to a subject and optionally an additional anticancer agent, but not for preventing cancer recurrence.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-3, 7-9, 12, 16-20, 23, 24, 26-29, 33, and 35 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Neri (Phase II Trial of Weekly Intravenous Gemcitabine Administration With Interferon and Interleukin-2 Immunotherapy for Metastatic Renal Cell Cancer, 2002, The Journal of Urology, pgs. 1-3; see instant PTO-892), as evidenced by T Ng (Alpha and beta type 1 interferon signaling: passage for diverse biologic outcomes, 2017, Cell, pgs. 349-352; see instant PTO-892) and Zhang (Emerging mechanisms and implications of cGAS-STING signaling in cancer immunotherapy strategies, 2024, Cancer Biol Med, pgs. 45-64; see instant PTO-892).
Regarding claims 1, 7, 23, 24, 26-28 and 35, Neri teaches treating subjects diagnosed with metastatic renal cell carcinoma patients with a pharmaceutical combination (pg. 2, “Results”) comprising an interferon-based therapeutic agent, namely IFN-α, and anti-cancer agents, namely gemcitabine and interleukin two (IL-2) (pg. 2, “Materials and Methods”) to prevent cancer recurrence. Regarding claim 12 and 33, as evidenced by Zhang, chemotherapy agents, such as, gemcitabine activate the cGAS-STING pathway. Cancer recurrence was prevented in one patient for 24 months (pg. 2, “Results”, fourth line). Regarding claims 8 and 29, as evidenced by T Ng, IFN-α is a Type I interferon; therefore, regarding claim 9, under broadest reasonable interpretation, IFN-α is a derivative of an interferon. Regarding claims 16, 18, 19, Neri teaches that the duration of each consecutive courses of IFN-α was two consecutive weeks, where IFN-α was administered at a dose of 3 million units (MU) three times a week (pg. 2, “Materials and Methods”). Regarding claims 2, 3 and 20, Neri teaches that there are six consecutive courses because the courses are repeated every month for six months (pg. 2, “Materials and Methods”); therefore, regarding claims 16-19, the interval between consecutive courses is two weeks.
Claim(s) 1-4, 6-9, 12, 16, 18, 20-23, 25-30, 33 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ikeda (Interferon Beta Prevents Recurrence of Hepatocellular Carcinoma After Complete Resection or Ablation of the Primary Tumor—A Prospective Randomized Study of Hepatitis C Virus–Related Liver Cancer, 2000, Hepatology, pgs. 228-232; see instant PTO-892), as evidenced by T Ng (Alpha and beta type 1 interferon signaling: passage for diverse biologic outcomes, 2017, Cell, pgs. 349-352; see instant PTO-892) and Tong (Activation of the cGAS-STING-IRF3 Axis by Type I and II Interferons Contributes to Host Defense, 2024, Advanced Science, abstract; see instant PTO-892).
Regarding claims 1,4, 6, 7, 23, 25-28, Ikeda teaches administration of an interferon-based therapeutic agent, namely interferon beta (IFN-beta) (pg. 229, left side, second paragraph), to prevent cancer recurrence in patients who had undergone potentially curative surgery or percutaneous ethanol injection therapy (pg. 228, right side, middle of last paragraph) for hepatitis C virus (HCV) related hepatocellular carcinoma (HCC) (pg. 1, right side, last three lines of second paragraph) and are in complete remission (pg. 230, right side, second paragraph). Regarding claim 26, under broadest reasonable interpretation, percutaneous ethanol injection therapy is an additional anticancer agent; the administration of IFN-beta and percutaneous ethanol injection therapy is a pharmaceutical combination, as demonstrated by the fact it actively treated patients (Fig. 1) and both IFN-beta and ethanol were injected (pg. 228, right side, middle of last paragraph; pg. 229, left side, second paragraph), which necessarily requires that it was sterile. Regarding instant claims 8 and 29, as evidenced by T Ng, IFN-beta is a type I interferon; therefore, regarding instant claim 9 and 30, IFN-beta is an interferon derivative. Furthermore, regarding claims 12 and 33, as evidenced by Tong, IFN-beta activates the STING signaling pathway. Regarding claims 16 and 18, Ikeda teaches each consecutive course is a week-long, where IFN-beta is administered in a dose of 6 million units (MU) twice a week (pg. 229, left side, second paragraph); this dosing regimen reads on the definition of “consecutive treatment course” in the specification ( pg. 9, second paragraph) because the prevention of cancer recurrence demonstrated in Ikeda (Fig. 1) necessarily requires than an effective concentration of IFN-Beta was maintained each week. Regarding claims 2, 3, and 20, Ikeda teaches that IFN-beta is administered for 144 consecutive courses, because the consecutive course is every week for 36 months (pg. 229, left side, second paragraph). Regarding claims 21 and 22, a week-long consecutive course schedule for 36 months, as taught by Ikeda, necessarily requires that the duration of consecutive courses is the substantially the same (i.e. one week) and the interval between the consecutive courses are substantially the same (i.e. zero days). Ikeda teaches that recurrence of HCC cancer was significantly higher in the control group than in patients receiving IFN-beta; 9 of the ten patients receiving IFN-beta did not have cancer recurrence over a 25 month period (pg. 230, left side, second paragraph; last line of Table 2).
Claim(s) 26, 27, 33, and 34 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang (Targeting Stimulator of Interferon Genes (STING): A Medicinal Chemistry Perspective, 2019, J. Med. Chem., pgs. 3785-3816; see instant PTO-892).
Zhang teaches a pharmaceutical combination comprising sting agonist MK-1454 and an immune checkpoint inhibitor Keytruda for treating cancer reoccurrence in a subject (pg. 3799, right side last paragraph). Zhang teaches 6 of 24 patients responded to the combination (pg. 3799, right side last paragraph).
Claim(s) 1-3, 7, 9, 12, 14, 16-24, 26-28, 30, 33 and 35 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Windbichler (Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase III trial, 2000, pgs. 1138-1144; see instant PTO-892) as evidenced by Zhang (Emerging mechanisms and implications of cGAS-STING signaling in cancer immunotherapy strategies, 2024, Cancer Biol Med, pgs. 45-64; see instant PTO-892) and Fuchs (The role of neopterin as a monitor of cellular immune activation in transplantation, inflammatory, infectious, and malignant diseases, 1992, Crit Rev Clin Lab Sci., abstract; see instant PTO-892).
Regarding claims 1, 7, 9, 14, 23-24, 26-28, 30 and 35, Windbichler teaches administration of a pharmaceutical combination comprising interferon-gamma, cisplatin, and cyclophosphamide to patients who had undergone primary surgery for FIGO stage Ic–IIIc ovarian cancer (abstract). The combination of interferon-gamma, cisplatin, and cyclophosphamide is a pharmaceutical combination, as demonstrated by the fact it actively treated patients (pg. 1141, “Survival”, first paragraph) and IFN-gamma and cisplatin were administered subcutaneously and intravenously, respectively (pg. 1139, “Randomization and treatment”), which necessarily requires that each were sterile. Regarding claims 12 and 33, evidenced by Zhang, cisplatin activates the cGAS-STING pathway. Regarding claims, 16-18, Windbichler teaches the duration of consecutive treatment courses is a week, where IFN-gamma is administered three times a week and teaches that the interval between consecutive treatment courses is a week (pg. 1139, “IFN treatment”, first paragraph). Regarding claim 19, “about” is not defined in the specification; under broadest reasonable interpretation, the weeklong duration and interval taught by Windbichler reads on the recited limitation of “about two weeks” for the interval and duration in claim 19. Regarding claims 2, 3 and 20, Windbichler teaches a total of 12 consecutive treatment courses (i.e. every other week for 6 months) (pg. 1139, right side, “Randomization and treatment”, last paragraph). Regarding claims 21 and 22, the dosing regimen of IFN-gamma three times weekly every other week necessarily requires that the durations of consecutive treatment courses as well as the interval between them is substantially the same. Windbichler teaches a complete response in 68% of subjects in the experimental condition (pg. 1141, left side, first paragraph) and significantly higher progression free survival at three years (Figure 1).
Regarding claim 14, the administration of IFN-gamma in the method of Windbichler would necessarily result in increased concentration of neopterin in the subject, relative to the concentration prior to the first administration, for substantially the entire course. As evidenced by Fuchs, IFN-gamma induces neopterin production; therefore, any administration of IFN-gamma to a subject would necessarily result in a higher concentration of neopterin in the subject relative to the neopterin concentration before IFN-gamma treatment. Thus, IFN-gamma administration in the Windbichler method would cause an increase in neopterin concentration in the subject. Neopterin concentration would remain higher in the subject for substantially the entire course because Windbichler teaches dosing the subject with IFN-gamma three times a week; each dose would induce neopterin production, resulting in elevated neopterin concentration for the duration of the treatment course in comparison to neopterin concentration prior to IFN-gamma treatment.
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.
Claim(s) 1, 4, and 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ikeda (Interferon Beta Prevents Recurrence of Hepatocellular Carcinoma After Complete Resection or Ablation of the Primary Tumor—A Prospective Randomized Study of Hepatitis C Virus–Related Liver Cancer, 2000, Hepatology, pgs. 228-232) as applied to claim 1 above, and further in view of Okusaka (Immunotherapy for hepatocellular carcinoma: current status and future perspectives, 2018, ESMO Open, pgs. 1-6; see instant PTO-892).
The teachings of Ikeda are described above. Ikeda teaches a method of treating HCC recurrence by administering IFN-beta (pg. 229, left side, second paragraph) to patients in complete remission (pg. 230, right side, second paragraph) from HSV related HCC after they have been treated with curative surgery (pg. 228, right side, middle of last paragraph).
Ikeda does not teach that the anticancer treatment is a combination of chemotherapy and immunotherapy.
Okusaka teaches several clinical trials for PD-L1 antibody treatment for HCC and that the results “are highly anticipated” (abstract). Nivolumab has been successful in treating HCC in early clinical trials (pg. 1, right side, last paragraph; second page). Okusaka teaches Phase III clinical trials exploring pembrolizumab, another anti-PD-L1 antibody, as a second line treatment for HCC in patients previously treated with chemotherapy (pg. 3, paragraph 3). Okusaka also teaches that “anticancer response to PD-L1 inhibitors might be enhanced if these drugs were to be used in combination with other treatments” (pg. 3, right side, second to last paragraph). For example, Okusaka teaches a study evaluating pembrolizumab used in combination with transcatheter arterial chemoembolisation (TACE) (pg. 5, left side, second to last paragraph).
It would be obvious to modify the step of achieving patient remission through surgery in the method of preventing HSV-related HCC recurrence of Ikeda with a combination of TACE and anti-PD-L1 immunotherapy, in order to arrive at a method of treating HCC recurrence by treating a patient who is in remission following combination treatment of TACE and PD-L1 immunotherapy, with IFN-Beta. One of ordinary skill would be motivated to achieve remission from a combination of TACE and PD-L1 antibody therapy as an alternative to surgery because some individuals may not qualify for surgical resection (ex. the cancer has spread or a tumor is too large). There would be a reasonable expectation of success applying the method of achieving cancer remission through a combination of TACE and PD-L1 to the method of preventing cancer using IFN-beta, because i) Okusaka explicitly teaches that combination therapy is expected to have a synergistic effect, ii) PD-L1 antibodies have been successful in HCC in early clinical trials (pg. 1, right side, last paragraph; second page).
Claim(s) 1, 9, 10, 11, 15, 26, 27, 30, 31, and 32 is/are rejected under 35 U.S.C. 103 as being unpatentable Ikeda (Interferon Beta Prevents Recurrence of Hepatocellular Carcinoma After Complete Resection or Ablation of the Primary Tumor—A Prospective Randomized Study of Hepatitis C Virus–Related Liver Cancer, 2000, Hepatology, pgs. 228-232) as applied to claim 1 above and further in view of Davis (Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial, 1989, N Engl J Med., abstract; see instant PTO-892) in further view of Choueiri (Evolving role of pegylated interferons in metastatic renal cell carcinoma, 2014, Experiment review of Anticancer Therapy, abstract; see instant PTO-892), as evidenced by FDA, (PEG-IntronTM (Peginterferon alfa-2b)Powder for Injection, Schering Corporation- Package Insert, 2003, pgs. 1-19; see instant PTO-892).
The teachings of Ikeda are described above. Ikeda teaches a method of treating HCC recurrence by administering IFN-beta twice a week in a dose of 6 million units for 36 months (pg. 229, left side, second paragraph) to patients in complete remission (pg. 230, right side, second paragraph) from HSV related HCC after they have been treated with curative percutaneous ethanol injection therapy (pg. 228, right side, middle of last paragraph)..
Ikeda does not teach that the interferon administered is pegylated or IFN-α-2b.
Davis teaches that interferon-alpha can also be used to eliminate chronic hepatitis C (abstract).
Choueiri teaches that pegylated IFN-α-2b has “greater efficacy with similar safety and tolerability to nonpegylated IFNs” in patients with hepatitis C and required less frequent administration (abstract).
It would be obvious to substitute the interferon-beta in the method of preventing HCC recurrence in hepatitis C virus (HCV) related HCC patients who had been treated with percutaneous ethanol injection therapy, were in remission, and were administered IFN-beta twice a week, as taught by Ikeda, with pegylated IFN-α-2b, as taught by Choueriri, to arrive at a method of preventing HCV-related HCC recurrence wherein the patient is in remission after curative percutaneous ethanol injection therapy and is administered pegylated IFN-α-2b twice a week. One of ordinary skill in the art would be motivated to substitute IFN-beta with pegylated IFN-α-2b, because it is more effective. There would be a reasonable expectation of success preventing HCV related HCC recurrence by administering pegylated IFN-α-2b twice a week to HSV-related HCC patients in remission after curative percutaneous ethanol injection therapy because i) Ikeda teaches HCV can cause HCC, ii) Davis teaches that IFN-alpha can eliminate HCV, and iii) Choueiri teaches that pegylated version of an IFN-alpha type, namely IFN-α-2b, is more effective treating the HCV patient population than the unpegylated version.
Regarding claim 15, as evidenced by FDA, the elimination half-life of pegylated IFN-α-2b is roughly 40 hours (pg. 2, “Pharmacokinetics”, first paragraph). If administered twice a week (i.e. roughly every 84 hours), as taught by the modified method of Ikeda, Davis, and Choueiri, the duration of the consecutive course would be from the first to the last administration plus roughly 2 half-lives of pegylated IFN-α-2b.
Claim(s) 1, 2, 12 and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lu (Engineered PLGA microparticles for long-term, pulsatile release of STING agonist for cancer immunotherapy, Cancer, 2020, pgs. 1-16; see instant PTO-892) in view of Zhang (Targeting Stimulator of Interferon Genes (STING): A Medicinal Chemistry Perspective, 2019, J. Med. Chem., pgs. 3785-3816; see instant PTO-892).
Lu teaches engineered polylactic-co-glycolic acid (PLGA) microparticles filled with the STING agonist Cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) (referred to in the art as cGAMP-MPs) (pg. 1, right side, first paragraph; pg. 3, right side, second paragraph) which release cGAMP in individual doses over time (Fig. 1; pg. 2, second paragraph). Lu teaches that cGAMP-MPs prevented tumor recurrence after surgery in a mouse model of melanoma (pg. 8, left side, middle of third paragraph, 6C). Lu teaches that this method of STING agonist administration reduces patient burden, and cost, while increasing effectiveness and ability to treat hard to reach tumors (pg. 10, right side, last paragraph). Lastly, Lu teaches “the modularity of this platform makes it easily compatible with loading any hydrophilic drug and many hydrophobic drugs…or even delivering various drugs at different times for combination cancer therapies” (pg. 11, left side, first paragraph).
Lu does not teach that the microparticles contain the STING agonist MK-1454.
Zhang teaches a pharmaceutical combination comprising sting agonist MK-1454 and an immune checkpoint inhibitor Keytruda for treating cancer reoccurrence in a subject (pg. 3799, right side last paragraph). Zhang teaches 6 of 24 patients responded to the combination (pg. 3799, right side last paragraph), which Zhang teaches prompted a second .
It would be obvious to combine the cancer treatment combination comprising STING agonist MK-1454 and a PD-1 checkpoint inhibitor, as taught by Zhang, with the method of delivering STING agonists to treat cancer recurrence via PLGA microparticles, as taught by Lu, to arrive at a method of treating cancer recurrence in a subject by administering a) PLGA microparticles containing MK-1454, and b) a PD-1 checkpoint inhibitor, to a subject. One of ordinary skill in the art would be motivated to deliver the MK-1454 STING agonist via the PLGA microparticles taught by Lu in order to prevent cancer recurrence because Lu teaches that administration of a STING agonist via PLGA microparticles has numerous advantages, including ability to treat a wider breadth of cancers, reduction in patient burden, and ability to prevent cancer recurrence through timed low doses. There would be a reasonable expectation of success preventing cancer recurrence in a subject by administering PLGA microparticles containing MK-1454 as well as PD-1 checkpoint inhibitor because i) Zhang teaches the combination of MK-1454 and PD-1 checkpoint inhibitor led to robust antitumor responses in some patients, ii) cGAMP, the STING agonist taught by Ly, is functionally equivalent to MK-1454, iii) the PLGA microparticle delivery method is able to dose STING agonists in low and isolated doses to prevent side effects from chronic exposure, iii) Lu states that the PLGA microparticle can accommodate versatile drugs.
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.
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Claims 1-3, 7-11,16-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 5, 6, 12, 14, 15, 16, 17, 18, 22, 23, 24, 25 of copending Application No. 17/629,099 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘099 reference application are directed to a species of a method of treating cancer that is encompassed by the instant claimed method of treating cancer.
Regarding instant claims 1-3, 7-11, and 16-20, Claims 1, 4, 5, 6, 12, 14, 15, and 22-25 of ‘099 teaches a method for treating liver cancer by intermittently administering pegylated interferon-alpha 2b for a plurality of consecutive treatment courses, wherein the duration of treatment is 2-6 weeks and the interval between each treatment is 2-6 weeks, and administering an additional anticancer agent including gemcitabine. Regarding instant claims 20-22, claims 16-18 teach that the interferon based therapeutic agent is administered for 2-25 consecutive course treatments and that the durations of and intervals between the consecutive course treatments are the same.
Because the copending claims recite the teaching of the active method steps of the instant claims, the method of the instant claims is anticipated by the copending claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-3, 7-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of copending Application No. 18/099,664 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because are directed to a species of a method of treating cancer that is encompassed by the instant claimed method of treating cancer.
Regarding instant claims 1-3, 7-13, 23, 24, 25, claims 1-8, 19, 25 of the reference application teach a method of treating liver cancer comprising intermittently administering an interferon-based therapeutic agent, which can include MK-1454 (an agonist of the STINGs signaling pathway), or a pegylated Type I interferon, such as pegylated interferon-alpha 2b to a subject for a plurality of consecutive course treatments; it further teaches administering an additional anticancer agent, namely gemcitabine to a subject. Regarding instant claim 14, claim 9 of the reference application teaches that the interferon-based therapeutic agent is administered to maintain the concentration of neopterin in the subject higher than the concentration of neopterin prior to the first administration of the therapeutic, for substantially the entire course. Regarding instant claim 15, claim 10 of the reference application teaches that the duration of the consecutive treatment course is the time period from the first to the last administration, plus about 5 in vivo half-lives of the therapeutic agent. Regrading instant claims 16-19, claims 11-15 of the reference application teach that the duration and interval of the consecutive course treatment is about 2 to about 6 weeks. Regarding instant claims 20-21, claims 16-18 of the reference application teach that the interferon based therapeutic agent is administered for 2-25 consecutive course treatments and that the durations of and intervals between the consecutive course treatments are the same.
Because the copending claims teach the same active method steps of the instant claims, the method of the instant claims is anticipated by the copending claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-3, 7-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-34 of copending Application No. 18/273,323 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘323 reference application are directed to a species of a method of treating cancer that is encompassed by the instant claimed method of treating cancer.
Regarding instant claims 1-3, and 7-13, claims 1, 17-24 of the reference application teach a method of treating liver cancer by intermittently administering an interferon-based therapeutic agent, which can include MK-1454 (an agonist of the STINGs signaling pathway), or a pegylated Type I interferon, such as pegylated interferon-alpha 2b, to a subject for a plurality of consecutive course treatments; it further teaches administering an additional anticancer agent, such as gemcitabine, to a subject. Regarding instant claim 14, claim 3 of the reference application teaches that the interferon-based therapeutic agent is administered to maintain the concentration of neopterin in the subject higher than the concentration of neopterin prior to the first administration of the therapeutic, for substantially the entire course. Regarding instant claim 15, claim 4 of the reference application teaches that the duration of the consecutive treatment course is the time period from the first to the last administration, plus about 5 in vivo half-lives of the therapeutic agent. Regrading instant claims 16-19, claims 5-9 of the reference application teach that the duration and interval of the consecutive course treatment is about 2 to about 6 weeks. Regarding instant claims 20-21, claims 10-12 of the reference application teach that the interferon based therapeutic agent is administered for 2-25 consecutive course treatments and that the durations of and intervals between the plurality of consecutive course treatments are the substantially the same. Regarding instant claims 26-35, claims 25-34 of the reference application teach a pharmaceutical combination for use in treating cancer comprising an interferon-based therapeutic agent, which can include a pegylated Type I interferon, such as pegylated interferon-alpha 2b, or MK-1454 (an agonist of the STINGs pathway) and an anticancer agent, such as Gemcitabine.
Because the copending claims teach the same active method steps and composition elements of the instant claims, the method and pharmaceutical combination of the instant claims are anticipated by the copending claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 4-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
Claims 1-25 of copending Application No. 18/099,664 (hereafter ‘664)
Claims 1-34 of copending Application No. 18/273,323 (hereafter ‘323)
as applied to claim 1 above, and further in view of Ikeda (Interferon Beta Prevents Recurrence of Hepatocellular Carcinoma After Complete Resection or Ablation of the Primary Tumor—A Prospective Randomized Study of Hepatitis C Virus–Related Liver Cancer, 2000, Hepatology, pgs. 228-232) in further view of Okusaka (Immunotherapy for hepatocellular carcinoma: current status and future perspectives, 2018, ESMO Open, pgs. 1-6; see instant PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other.
The claims of the 18/099,664 and 18/273,323 references are described above.
The 18/099,664 and 18/273,323 references differ from the instant claims in the same way: they do not comprise treating a subject that is in complete remission or that has undergone a combination of chemotherapy and immunotherapy anti-cancer treatment.
The teachings of Ikeda are above.
The teachings of Okusaka are above.
It would be obvious to combine the method of administering an interferon-based therapeutic agent for treating cancer of 18/099,664, and 18/273,323 with the method of achieving complete remission via a combination of chemotherapy and immunotherapy of Okusaka to arrive at the instant method of administering an interferon-based therapeutic agent to a subject who is in complete remission after receiving anti-cancer treatment comprising a combination of chemotherapy and immunotherapy.
One of ordinary skill in the art would be motivated to combine the teachings of 18/099,664 and 18/273,323, with Okusaka because Ikeda teaches that interferon treatment, similar to those in the reference applications, can prevent cancer recurrence in an HCC patient population in complete remission after surgery, while Okusaka teaches chemotherapy and immunotherapy combinations as a promising route for treating HCC and is therefore an alternative for patients who may not qualify for curative surgery. There would be a reasonable expectation of success combining the method of administering an interferon-based therapeutic agent for treating cancer of 18/099,664 and 18/273,323 with the method of achieving complete remission via a combination of chemotherapy and immunotherapy, because of the successful results of Ikeda and because of Okusaka’s teachings on the promise of immunotherapy and chemotherapy combinations for HCC treatment. Applying the method of the reference applications to a patient population in complete remission via a combination of immunotherapy and chemotherapy is not a patentably distinct limitation.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 4-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
Claims 1, 4, 5, 6, 12, 14, 15, 16, 17, 18, 22, 23, 24, 25 of copending Application No. 17/629,099as applied to claim 1 above and in further view of Ikeda (Interferon Beta Prevents Recurrence of Hepatocellular Carcinoma After Complete Resection or Ablation of the Primary Tumor—A Prospective Randomized Study of Hepatitis C Virus–Related Liver Cancer, 2000, Hepatology, pgs. 228-232) in further view of view of Davis (Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial, 1989, N Engl J Med., abstract; see instant PTO-892), in further view of Okusaka (Immunotherapy for hepatocellular carcinoma: current status and future perspectives, 2018, ESMO Open, pgs. 1-6; see instant PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other.
The claims of 17/629,099 are described above.
The 17/629,099 reference differs from the instant claims because it does not comprise treating a subject that is in complete remission or that has undergone a combination of chemotherapy and immunotherapy anti-cancer treatment.
The teachings of Ikeda are above.
The teachings of Davis are above.
The teachings of Okusaka are above.
It would be obvious to combine the method of administering an interferon-alpha for treating cancer of 17/629,099 with the method of achieving complete remission via a combination of chemotherapy and immunotherapy of Okusaka to arrive at the instant method of administering an interferon-alpha to a subject who is in complete remission after receiving anti-cancer treatment comprising a combination of chemotherapy and immunotherapy. One of ordinary skill in the art would be motivated to combine the teachings of 17/629,099 and Okusaka because interferon administration can prevent HCC recurrence for a period of time in patients already in remission, as taught by Ikeda, while Okusaka teaches that chemotherapy and immunotherapy combinations are a promising route to achieve HCC remission and therefore provides an alternative for patients who may not qualify for curative surgery. There would be a reasonable expectation of success because i) Ikeda teaches successful results treating HSV-related HCC recurrence by administering an interferon-beta, ii) Davis teaches that interferon-alpha can also be used to treat HSV and iii) because Okusaka teaches the promise of immunotherapy and chemotherapy combinations for HCC treatment.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims allowed.
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/MICHELLE CALLAHAN BUCCINI/Examiner, Art Unit 1675
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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