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 .
Claims Status
The Amendment filed on 01Dec2023 is acknowledged in which claim(s) 2 were canceled by Applicant.
Claim(s) 1 and 3-23 is/are currently pending and presented for examination on the merits.
Claim Rejections - 35 USC § 112(b)
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 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.
Claim(s) 1, 7-9, 13-23 is/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(s) 1, 7-9, 13-23, recite(s) “a standard therapy” in line(s) 8 of claim 1, rendering the claim(s) indefinite. The Applicant disclosure defines “The "standard therapy" in the present invention is a treatment whose therapeutic effect and safety have been confirmed by the results of many clinical trials and which is most recommended on the basis of scientific evidence…” [e.g., pg. 10, lines 32-34]. It is noted that “many” and “most” are terms of relative degrees that are unclear. Further, it is unclear if the phrase “a standard therapy” means (1) standard anywhere in the world (e.g., because standard of care can differ by county); (2) standard in only specific regions of the world (e.g. USA, EU, APAC, etc.); (3) how many clinical trials are required; (4) “most” is relative to only one other drug; (5) “most” is relative to only drugs in the same category (e.g., Ab to Ab, not Ab to Cell Therapeutic, etc.); (6) who decides what is “most” recommended (e.g., Scientists, Physicians, CDC, FDA, etc.); (7) the therapeutic has to treat cancer directly (e.g., Chemotherapy); (8) the therapeutic encompasses pretreatment, posttreatment, combinatorial, priming, and/or adjuvant interventions (e.g., ondansetron, etc.); or (9) something else. For the purposes of compact prosecution, the phrase “a standard therapy” will be considered to mean any therapy that has been reported in the prior art to be administered to a subject with cancer as part of the overall treatment regimen (e.g., encompassing anti-neoplastic, combination, adjuvant, priming, pretreatment, and/or post-treatment therapies). This rejection may be overcome by amending claim(s) 1 to clearly recite the limitation(s) of the instant invention. Claim(s) 7-9 and 13-23 can overcome this rejection by amending claim(s) 1 as recited above.
Regarding claims 4-6, the phrase(s) “(1x)”, “(1a)”, “(1b)”, “(1c)”, and “(1d)” is/are not defined in the terms preceding it. Thus, the phrase(s) “(1x)”, “(1a)”, “(1b)”, “(1c)”, and “(1d)” render(s) the claim(s) indefinite because it is unclear whether the limitation(s) in the parentheses are a part of the claimed invention. See MPEP 2173.05(d). It is unclear if “(1x)”, “(1a)”, “(1b)”, “(1c)”, and “(1d)” is/are limitation(s) or merely provided to delineate each of the distinct dosing limitation(s) of the claimed invention. To promote compact prosecution, the phrase(s) “(1x)”, “(1a)”, “(1b)”, “(1c)”, and “(1d)” is/are not considered a limitation of the claim(s). This rejection may be overcome by amending claims 4-6 to (1) replace the above phrases with standard bulleting conventions (e.g., “a)-e)”, “i)-v)”, etcetera), or (2) delete the above phrases.
Claim(s) 13, recite(s) “distant metastasis” in line(s) 2, rendering the claim(s) indefinite. Specifically, it is unclear if the phrase means metastatic cells are present in (1) an adjacent but distinct tissue (e.g., different organ, lymph node, etcetera); (2) a tissue a specific distance or greater from the primary tumor; or (3) something else. For the purposes of compact prosecution, the phrase will be considered to mean any metastasis. This rejection may be overcome by amending claim(s) 13 as recited above or to otherwise clearly recite the limitation(s) of the instant invention.
Claim Rejections - 35 USC § 112(a) – scope of enablement
Claim(s) 1 and 3-23 is/are 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 suppressing progression of and/or treating a solid cancer comprising the administration of a CD47 inhibitory substance and an immune checkpoint inhibitor wherein the subject receives or has received a standard therapy, does not reasonably provide enablement for suppressing recurrence of cancer comprising the same administration(s) described above. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation."' (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (A) The nature of the invention; (B) The breadth of the claims; (C) The amount of direction provided by the inventor; (D) The existence of working examples; (E) The state of the prior art; (F) The level of predictability in the art; (G) The quantity of experimentation needed to make or use the invention based on the content of the disclosure and (H) The level of one of ordinary skill. While all of these factors are considered, a sufficient amount for amount for a prima facie case are discussed below.
The nature of the invention
Claims 1 and 3-23 is/are drawn to a method for suppressing progression of, suppressing recurrence of, and/or treating a solid cancer comprising the administration of a CD47 inhibitory substance and an immune checkpoint inhibitor wherein the subject receives or has received a standard therapy.
The breadth of the claims
The claim is broad in that it encompasses the suppression of the recurrence of all solid cancers.
The instant specification discloses “…the "suppression of recurrence" of cancer means to prevent the recurrence of cancer in a patient whose cancer lesion has completely or substantially disappeared or removed by cancer treatment or resection surgery.” [e.g., ¶ 0062].
As the instant disclosure does not define the term “preventing”, the ordinary meaning prevent, “to keep from happening or existing”, as defined by Merriam-Webster (Dictionary webpage, 24 Apr 2025) is applied.
The claim is inclusive of all types of solid cancers (e.g., skin cancer, breast cancer, adamantinomas, chondroma, osteosarcomas, thyroid cancer, pancreatic cancer, teratomas, Wilms tumors, hepatoblastomas, neuroblastomas, lung cancer, bladder cancer, etcetera). The breadth of the claim exacerbates the complex nature of the subject matter to which the instant claims are directed. Solid cancers are not a single disease, or cluster of closely related disorders. There are numerous solid cancer, which have some commonality (e.g., loss of controlled growth). Despite the broad related grouping of ‘solid cancers’, these diseases are heterogeneous at both the molecular and clinical level (e.g., melanomas, sarcomas, glioblastomas). Each type of solid cancer also have subtypes with unique etiological and physiological characteristics.
The amount of direction provided by the inventor/the existence of working examples
The examples of the instant disclosure studied the anti-tumor effect(s) include: (1) a multi-center, open-label, uncontrolled study for evaluating tolerability, safety, and efficacy when combination in which Magrolimab or Nivolumab described below is used in combination with a combination therapy in which Bevacizumab or Cetuximab is added to FOLFOX therapy was applied to patients with radically unresectable advanced or recurrent colorectal cancer; wherein the disclosed results include safety and efficacy evaluations [e.g., ¶ 0075-0105; fig. 1]; and (2) a multi-center, open-label, uncontrolled study for evaluating tolerability, safety, and efficacy when combination in which Magrolimab or Nivolumab described below is used in combination with mFFX therapy was applied to patients having distant metastasis; wherein the disclosed results include safety and efficacy evaluations [e.g., ¶ 0106-; fig. 2].
The examples provided do not demonstrate the prevention of recurrence of solid cancers. Additionally, the disclosure does not discuss, or demonstrate through working examples, a method that could be used to determine that the recurrence of solid cancer was prevented using claimed method as there is no disclosed method to determine which (if any) of the solid cancer(s) would have predictably reoccurred following treatment.
The state of the art/the level of predictability in the art
There are no methods to establish that the occurrence of primary tumors or the suppression of recurrence of tumors can be prevented using the claimed therapeutic method in the prior art. Additionally, there are no methods that could be used to identify subjects who would have predictably developed hematological tumors in order to determine that the primary tumors were prevented using the claimed methods.
One of ordinary skill in the art would understand that there are risk factors associated with certain cancers, and that an individual can lower their risk of cancer(s) but there is no sure way to prevent cancer, as evidenced by the American Cancer Society (Cancer Risk and Prevention webpage, 21 Mar 2025).
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Studies regarding the treatment and prevention of cancer are underway to improve early detection and provide better treatments. However, based on the instant disclosure and prior art, there is no known method through which one of ordinary skill in the art would have been able to reliably predict which subject(s) would have predictably had cancer(s) recur in order to determine that the cancer(s) was/were prevented using the instant claimed methods. Therefore, in order to practice the invention as claimed, one of ordinary skill in the art would have to perform undue experimentation to develop a method which accurately predicts cancer prevention. Applicant is enabled for treatment and suppressing progression of solid cancer.
Conclusion
In view of the Wands factors as discussed above, one of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the instant claimed invention. As such, instant claims 1 and 3-23 were determined to not meet the scope of enablement requirement of 35 USC § 112(a).
Enablement can be met by amending claim(s) 1 to (I) remove phrases regarding “suppression of recurrence” of cancer; or (II) provide evidence of suppression of recurrence of cancer as a result of the instant claimed method(s) (e.g., clinical trial results showing reduction in the rate of recurrence versus a control arm). Claim(s) 3-23 can overcome this rejection by amending claim(s) 1 as described above.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1, 9, 14-19 is/are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by US 2021/0047416 A1 (Published 18Feb2021, Effective Filing Date 18Oct2017; hereinafter “US416”).
Regarding instant claim(s) 1, 15-16, 19, US416 teaches the treatment of solid cancer(s) (e.g., ovarian cancer) comprising the administration of an anti-CD47 antibody and an anti-PD-L1 (e.g., immune checkpoint inhibitor) antibody [e.g., title, abstract; ¶ 0003-0007, 0012, 0062, 0103]. US416 further teaches the anti-CD47 antibody is Hu5F9-G4 (e.g., Magrolimab) [e.g., ¶ 0013, 0015; tbl. 2], and embodiments further comprising at least one additional reagent such as a chemotherapeutic drug (e.g., ‘standard therapy’, see 112(b) rejection above) [e.g., ¶ 0126].
Regarding instant claim(s) 9, 14, US416 further teaches solid tumor patients are checkpoint-naïve (e.g., no prior CD47 or PDL1 therapy; e.g., no prior systemic therapy) [e.g., ¶ 0146].
Regarding instant claim(s) 17-18, US416 further teaches the anti-CD47 antibody (e.g., Magrolimab) is administered a 1 mg/kg priming dose on Day 1 and a 30 mg/kg maintenance dose on Days 8 and 22 (e.g., second and subsequent weekly administrations) [e.g., tbl. 2]. US416 further teaches the anti-CD47 antibody is administered weekly [e.g., ¶ 0020, 0113, 0115]. US416 further teaches the anti-CD47 antibody (e.g., Magrolimab) is administered intravenously [e.g., ¶ 0018, 0054-0055; claim 19].
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 3-5 is/are rejected under 35 U.S.C. 103 as being unpatentable over anticipated by US 2021/0047416 A1 (hereinafter “US416”) as applied to claim(s) 1 above, and further in view of Wang et al. (World J Clin Cases 2021 April 16; 9(11): 2533-2541; hereinafter “Wang”).
The teachings of US416 as recited above for are applied for claim(s) 1.
US416 does not expressly teach that (1) the standard therapy comprises FOLFOX and bevacizumab, wherein (1) FOLFAX comprises 5-Fu, levofolinate, and oxaliplatin, and (2) every 2 weeks in a series of administrations, bevacizumab is administered intravenously at 5 mg/kg, oxaliplatin is administered intravenously at 85 mg/m2, levofolinate calcium is administered at 200 mg/m2, 5-FU is administered at 400 mg/m2, and further continuously administering 5-FU at 2400 mg/m2.
Regarding instant claim(s) 3, Wang teaches the gastrointestinal cancer FOLFOX (e.g., chemotherapy) and bevacizumab treatment regimen as an effective therapy for ovarian mucinous cancer (e.g., a type of ovarian cancer) and that ovarian mucinous carcinoma patients could benefit from FOLFOX and bevacizumab treatment [e.g., abstract, conclusion]. Wang further teaches that FOLFOX comprises 5-Fu, levofolinate, and oxaliplatin [e.g., treatment]. Regarding instant claim(s) 4-5, Wang teaches bevacizumab is administered at 5mg/kg, oxaliplatin is administered at 100 mg/m2, calcium levofolinate is administered at 400 mg/m2, and 5-Fu is administered at 400 mg/m2 at 2 week intervals [e.g., treatment].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to substitute the general chemotherapeutic agent(s) in the method of treating ovarian cancer comprising administering Magrolimab and immune-checkpoint inhibitor (ICI) agents wherein the subject additionally receives or has received chemotherapy as taught by US416, with the FOLFOX and bevacizumab regimen for ovarian mucinous cancer as taught by Wang, to arrive at a method of treating ovarian cancers comprising the administration of Magrolimab and an ICI wherein the subject receives or has received FOLFOX and bevacizumab therapy. A PHOSITA would have been motivated to substitute the general chemotherapeutic agent(s) in the method of treating ovarian cancer comprising administering Magrolimab and immune-checkpoint inhibitor (ICI) agents wherein the subject additionally receives or has received chemotherapy as taught by US416, with the FOLFOX and bevacizumab regimen for ovarian mucinous cancer as taught by Wang, because US416 teaches the method, both US416 and Wang teach the overlapping use of chemotherapy agents in the treatment of ovarian cancers, and Wang teaches specifically that FOLFOX and bevacizumab are effective ovarian mucinous cancer therapies and suggests patients could benefit from gastrointestinal-type chemotherapy (e.g., FOLFOX and bevacizumab). Further, MPEP 2144.06(I) provides “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)”. There would have been a reasonable expectation of success for a PHOSITA to substitute the general use of chemotherapy regimen(s) in the method of treating ovarian cancer comprising administering Magrolimab and immune-checkpoint inhibitor (ICI) agents wherein the subject additionally receives or has received chemotherapy as taught by US416, with the FOLFOX and bevacizumab regimen for ovarian mucinous cancer as taught by Wang, because US416 teaches the method comprising chemotherapy, both US416 and Wang teach the treatment of ovarian cancer, and Wang teaches FOLFOX and bevacizumab as an effective therapy for ovarian mucinous cancer (e.g., a type of ovarian cancer). This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Further, it would have been obvious to a PHOSITA to modify the modified method of treating ovarian cancers comprising the administration of Magrolimab and an ICI wherein the subject receives or has received FOLFOX and bevacizumab therapy of US416 and Wang (see above) to include that every 2 weeks in a series of administrations, bevacizumab is administered intravenously at 5 mg/kg, oxaliplatin is administered intravenously at 85 mg/m2, levofolinate calcium is administered at 200 mg/m2, 5-FU is administered at 400 mg/m2, and further continuously administering 5-FU at 2400 mg/m2. In regard to the specific dosage(s) and interval amounts recited in the instant claims "[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, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that treatment (i.e. dosage and intervals) optimization is obvious.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over anticipated by US 2021/0047416 A1 (hereinafter “US416”) and Wang et al. (World J Clin Cases 2021 April 16; 9(11): 2533-2541; hereinafter “Wang”) as applied to claim(s) 1 and/or 4 above, and further in view of Singh et al. (Genes and Diseases (2021) 8, 133-145. Available online 30 Oct 2019; hereinafter “Singh”).
The teachings of US416 and Wang as recited above for are applied for claim(s) 1 and 4.
US416 and Wang do not expressly teach that (1) the standard therapy comprises FOLFOX and cetuximab, wherein FOLFAX comprises 5-Fu, levofolinate, and oxaliplatin, and wherein every 2 weeks in a series of administrations, cetuximab is first administered intravenously at 400 mg/m2 and subsequently administered at 250 mg/m2, oxaliplatin is administered intravenously at 85 mg/m2, levofolinate calcium is administered at 200 mg/m2, 5-FU is administered at 400 mg/m2, and further continuously administering 5-FU at 2400 mg/m2.
Regarding instant claim(s) 6, Singh teaches FOLFOX and cetuximab as an effective colorectal cancer (e.g., a type of gastrointestinal cancer) regimen [e.g., pgs. 138-139, “Treatment based on CMS1…”].
Further, it would have been obvious to a PHOSITA to modify the modified method of treating ovarian cancers comprising the administration of Magrolimab and an ICI wherein the subject receives or has received FOLFOX and bevacizumab of US416 and Wang (see above) to include that the FOLFOX may be administered wit cetuximab (e.g., instead of bevacizumab) as taught by Singh, because US416 and Wang teach the method of treating ovarian cancers comprising the administration of FOLFOX and bevacizumab, Wang teaches that “gastrointestinal chemotherapy regimens” may be useful in ovarian cancers, and Singh teaches FOLFOX and cetuximab is an effective chemotherapy regimen in CRC (e.g., a type of gastrointestinal cancer). There is an expectation of success for a PHOPSITA to substitute the bevacizumab antibody in the modified method of treating ovarian cancers comprising the administration of Magrolimab and an ICI wherein the subject receives or has received FOLFOX and bevacizumab of US416 and Wang (see above) because US416 and Wang teach the method of treating ovarian cancers comprising the administration of FOLFOX and bevacizumab, Wang teaches that “gastrointestinal chemotherapy regimens” may be useful in ovarian cancers, and Singh teaches FOLFOX and cetuximab is an effective chemotherapy regimen in CRC (e.g., a type of gastrointestinal cancer). This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 7-8 is/are rejected under 35 U.S.C. 103 as being unpatentable over anticipated by US 2021/0047416 A1 (hereinafter “US416”) as applied to claim(s) 1 above, and further in view of Nagata et al. (Int. J. Mol. Sci. 2021, 22, 2690, 07Mar2021; hereinafter “Nagata”).
The teachings of US416 as recited above apply for claim(s) 1.
Regarding instant claim(s) 3, US416 further teaches the cancer may comprise colon cancer (e.g., from among a list of solid cancers) [e.g., ¶ 0062, 0103], but does not provide rationale for selection of colon cancer from the list.
US416 does not expressly teach that the solid cancer is radically unresectable advanced colorectal cancer.
Regarding instant claim(s) 7-8, Nagata teaches colorectal cancers (CRC) express CD47, that increased CD47 expression is associated with poorer prognosis/survival and that metastatic and incompletely resected CRCs (e.g., radically unresectable colorectal cancer) express CD47 [e.g., pg. 10, “5. Conclusions”; fig. 4; tbls. 1, 3]. Nagata further teaches that anti-CD47 antibodies including Hu5F9-G4 (e.g., Magrolimab) may be used in combination therapies for treating CRCs [e.g., pg. 9, ¶ 1; pg. 10, “5. Conclusions”].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to combine the colon cancer indication in the method of treating solid tumors comprising administration of Magrolimab and an immune checkpoint inhibitor (ICI) wherein the subject receives or has received a standard therapy as taught by US416 (see above), with the colorectal cancer indications as taught by Nagata, to arrive at a method of treating radically unresectable advanced colorectal cancer comprising administration of Magrolimab and an ICI wherein the subject receives of has received a standard therapy. A PHOSITA would have been motivated to combine the broader colon cancer indication (e.g., encompassing colorectal cancers) from the list of solid cancers in the method of treating solid cancer comprising administration of Magrolimab and an ICI wherein the subject receives of has received a standard therapy as taught by US416 with the metastatic (e.g., radically unresectable advanced) colorectal cancer indication as taught by Nagata, because US416 teaches the base method of treating solid cancer(s) comprising Magrolimab (e.g., Hu5F9-G4) administration and that the solid cancer indications include colon cancers, and Nagata teaches that metastatic CRCs (e.g., a type of colon cancer) express increased CD47 levels which are associated with poor prognosis and that anti-CD47 antibodies including Hu5F9-G4 (e.g., Magrolimab) may be useful in combination therapy treatment of CRCs. There would have been a reasonable expectation of success for a PHOSITA to combine the colon cancer indication (e.g., encompassing colorectal cancers) from the list of solid cancers in the method of treating solid cancer comprising administration of Magrolimab and an ICI wherein the subject receives of has received a standard therapy as taught by US416 with the metastatic (e.g., radically unresectable advanced) colorectal cancer indication as taught by Nagata, because US416 teaches the base method of treating solid tumors comprising administration of the anti-CD47 antibody Magrolimab (e.g., Hu5F9-G4) and that the cancer indications include colon cancer, and Nagata teaches that CRC (e.g., a type of colon cancer) express CD47, that increased CD47 expression is associated with poorer prognosis, that metastatic (e.g., radically unresectable) CRCs express CD47, and that anti-CD47 antibodies including Hu5F9-G4 (e.g., Magrolimab) may be useful in combination therapy treatment of CRCs. This rationale aligns with the principle of applying a known technique to a known method to yield predictable results, supporting a conclusion of obviousness (see MPEP § 2143).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 10-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over anticipated by US 2021/0047416 A1 (hereinafter “US416”) as applied to claim(s) 1 above, and further in view of Ludwig Cancer Research (Ludwig researchers target two types of pancreatic cancer webpage 2014; hereinafter “Ludwig”) and Marsh et al. (Cancer Medicine 2015, 4(6):853–863; hereinafter “Marsh”).
The teachings of US416 as recited above apply for claim(s) 1.
Regarding instant claim(s) 10-13, US416 further teaches the solid cancer may comprise pancreatic cancer (e.g., from among a list of solid cancers) [e.g., ¶ 0062, 0103], but does not provide rationale for selection of pancreatic cancer from the list.
US416 does not expressly teach (1) a method of treating metastatic pancreatic cancer comprising the administration of Magrolimab, and an immune checkpoint inhibitor, wherein the subject receives or has received FOLFIRINOX chemotherapy, wherein every 2 weeks in a series of intravenous administrations (a) oxaliplatin is administered intravenously at 85 mg/m2, levofolinate calcium is administered at 200 mg/m2, irinotecan hydrochloride hydrate is administered at 180 mg/m2, 5-FU is administered at 400 mg/m2, and further continuously administering 5-FU at 2400 mg/m2; or (b) oxaliplatin is administered intravenously at 85 mg/m2, levofolinate calcium is administered at 200 mg/m2, irinotecan hydrochloride hydrate is administered at 150 mg/m2, 5-FU is administered at 400 mg/m2, and further continuously administering 5-FU at 2400 mg/m2.
Regarding instant claim(s) 10-13, Ludwig teaches CD47 is elevated in pancreatic neuroendocrine tumor cells and pancreatic ductal adenocarcinoma cells, and blocking CD47 cause tumor regression [e.g., pg. 1, ¶ 1]. Ludwig further teaches targeting CD47 could provide a new approach for treating patients with pancreatic cancer [e.g., pg. 1, ¶ 3].
Regarding instant claim(s) 10-13, Marsh teaches FOLFIRINOX (e.g., chemotherapy) regimen is a superior treatment in metastatic pancreatic cancers [e.g., title, abstract; tbl. 3]. Marsh further teaches the FOLFIRINOX regimen comprises administration by infusion (e.g., intravenous) of oxaliplatin at 85 mg/m2, leucovorin (e.g., comprising levofolinate calcium) at 400 mg/m2, irinotecan (e.g., irinotecan hydrochloride hydrate) at 150 mg/m2, and 5-Fu in a bolus at 400 mg/m2 followed by continuous 5-FU at 2400 mg/m2, at 2 week intervals [e.g., pgs. 853-854, “FOLFIRINOX”], and further that specific dosing of FOLFIRINOX regimen may be modified [e.g., pg. 855; tbl. 2].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to select the pancreatic cancer indication and substitute the general chemotherapeutic agent(s) in the method of treating cancer comprising administering Magrolimab and immune-checkpoint inhibitor (ICI) agents wherein the subject additionally receives or has received chemotherapy as taught by US416, with the pancreatic cancer indications by CD47 targeting drugs as taught by Ludwig, and the FOLFIRINOX chemotherapy regimen for treating metastatic pancreatic cancers as taught by Marsh, to arrive at a method of treating metastatic pancreatic cancer comprising the administration of Magrolimab and an ICI wherein the subject receives or has received FOLFIRINOX therapy. A PHOSITA would have been motivated to select the pancreatic cancer indication and substitute the general chemotherapeutic agent(s) in the method of treating cancer comprising administering Magrolimab and immune-checkpoint inhibitor (ICI) agents wherein the subject additionally receives or has received chemotherapy as taught by US416, with the pancreatic cancer indications by CD47 targeting drugs as taught by Ludwig, and the FOLFIRINOX chemotherapy regimen for treating metastatic pancreatic cancers as taught by Marsh, because US416 teaches the method, both US416 and Ludwig teach pancreatic cancers are treatable using CD47 inhibiting agents, Ludwig teaches CD47 is a new and promising target for the treatment of pancreatic cancers, both US416 and Marsh teach the overlapping use of chemotherapy agents in the treatment of pancreatic cancers, and Marsh specifically teaches that FOLFIRINOX as an effective therapy for metastatic pancreatic cancers that is superior to other therapies. There would have been a reasonable expectation of success for a PHOSITA to motivated to select the pancreatic cancer indication and substitute the general chemotherapeutic agent(s) in the method of treating cancer comprising administering Magrolimab and immune-checkpoint inhibitor (ICI) agents wherein the subject additionally receives or has received chemotherapy as taught by US416, with the pancreatic cancer indications by CD47 targeting drugs as taught by Ludwig, and the FOLFIRINOX chemotherapy regimen for treating metastatic pancreatic cancers as taught by Marsh, because US416 teaches the method comprising CD47 antibody (e.g., Magrolimab) and chemotherapy administration and pancreatic cancer as an indication, Ludwig teaches CD47 targeted therapies are effective in treating pancreatic cancers, and Marsh teaches FOLFIRIFOX an effective therapy for metastatic pancreatic cancers. This rationale aligns with the principles of applying a known technique to a known method to yield predictable results and/or simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Further, it would have been obvious to a PHOSITA to modify the modified method of treating metastatic pancreatic cancer comprising the administration of Magrolimab and an ICI wherein the subject receives or has received FOLFIRINOX therapy of US416, Ludwig, and Marsh (see above) to include the FOLFIRINOX chemotherapy is administered intravenously in a series every 2 weeks comprising (a) oxaliplatin is administered intravenously at 85 mg/m2, levofolinate calcium is administered at 200 mg/m2, irinotecan hydrochloride hydrate is administered at 180 mg/m2, 5-FU is administered at 400 mg/m2, and further continuously administering 5-FU at 2400 mg/m2; or (b) oxaliplatin is administered intravenously at 85 mg/m2, levofolinate calcium is administered at 200 mg/m2, irinotecan hydrochloride hydrate is administered at 150 mg/m2, 5-FU is administered at 400 mg/m2, and further continuously administering 5-FU at 2400 mg/m2. In regard to the specific dosage(s) and interval amounts recited in the instant claims "[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, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that treatment (i.e. dosage and intervals) optimization is obvious.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 20-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over anticipated by US 2021/0047416 A1 (hereinafter “US416”) as applied to claim(s) 1 above, and further in view of US416 (Opdivo (Nivolumab) product insert, Jan2021; hereinafter “FDA”).
The teachings of US416 as recited above apply for claim(s) 1.
US416 does not expressly teach the immune checkpoint inhibitor is nivolumab wherein the nivolumab is administered at 480 mg intravenously every 4 weeks.
Regarding instant claim(s) 20-22, US416 further teaches Two other FDA-approved checkpoint inhibitors, nivolumab and pembrolizumab work in a similar way, but they target PD-1 (e.g., the other side of the PD1/PDL1 axis) [e.g., ¶ 0007].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) to try Nivolumab as the immune checkpoint inhibitor (ICI) in the method of treating solid cancer comprising administration of Magrolimab and an ICI wherein the subject receives or has received chemotherapy US416 to arrive at the instant invention of a method of treating solid cancer comprising administration of Magrolimab and Nivolumab wherein the subject receives or has received chemotherapy. This conclusion of obviousness is based on the 'obvious to try rationale'. There is/are only 2 possible individual substitutions disclosed by US416 for anti-PD1 antibody, and US416 discloses that these antibodies work “similarly” to the ICI (PDL1 antibody) in the examples of the invention. Further, a skilled artisan would understand Nivolumab and Pembrolizumab were well known in the art, and FDA approved in a variety of solid tumor indications, and under investigation for additional indication(s). Therefore, it would also be obvious for a skilled artisan to try Nivolumab and Pembrolizumab as ICIs that were not expressly tested in US416 to determine which combination(s) with Magrolimab are optimal, which is well within the purview of those in the art. This rationale aligns with choosing from a finite number of identified, predictable solutions with a reasonable expectation of success; see MPEP 2143(I)(E).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over anticipated by US 2021/0047416 A1 (hereinafter “US416”) as applied to claim(s) 1 and 20-22 above, and further in view of FDA (Opdivo (Nivolumab) product insert, Jan2021; hereinafter “FDA”).
The teachings of US416 as recited above apply for claim(s) 1 and 20-22.
Regarding instant claim(s) 23, US416 further teaches the cancer indications treatable with the disclosed method(s) include a variety of solid tumors including but not limited to melanoma, lung cancer, renal cancer, head and neck cancer, urothelial cancer, and hepatocellular carcinoma [e.g., ¶ 0062, 0103].
US416 does not expressly teach that the nivolumab is administered at 480 mg intravenously every 4 weeks.
Regarding instant claim(s) 23, FDA teaches Nivolumab is approved for intravenous administration every 4 weeks at a flat dose of 480 mg in a variety of solid tumor indications including but not limited to melanoma, lung cancer, renal cancer, head and neck cancer, urothelial cancer, and hepatocellular carcinoma.
Further, it would have been obvious to a PHOSITA to modify the modified method of treating solid cancer comprising administration of Magrolimab and Nivolumab wherein the subject receives or has received chemotherapy as taught by US416 (see above) to include that nivolumab is administered at 480 mg intravenously every 4 weeks as taught by FDA, because US416 teaches the method comprising nivolumab administration treats a variety of cancers that overlap with a number of the FDA-approved nivolumab indications at the recited dose schedule. There is an expectation of success for a PHOPSITA to combine the modified method of treating solid cancer comprising administration of Magrolimab and Nivolumab wherein the subject receives or has received chemotherapy as taught by US416, with the Nivolumab administration of 480 mg intravenously every 4 weeks as taught by the FDA, because US416 teaches the method comprising nivolumab administration treats a variety of cancers that overlap with a number of the FDA-approved nivolumab indications at the recited dose schedule. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are currently allowed.
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/AMY M. CHATTIN/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
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