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 .
Status of Claims
Claims 1-20 are currently under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The U.S. effective filing date of all claims under examination is set at 08/18/2021 based on the provisional application 63/068,172 (filed 08/18/2021).
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/16/2023 is being considered by the examiner.
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." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because of the following informalities:
Fig. 5 (Pg. 7/20) The black and white drawing submitted does not show the red coloration described on Pg. 5 Paragraph [0022] of the specification for the genes in red in the MA plot.
Fig. 6 (Pg. 10/20) The black and white drawing submitted does not show the red coloration described on Pg. 6, Paragraph [0023] of the specification for the immunofluorescence by F4/80.
Specification
The disclosure is objected to because of the following informalities:
On Pg. 4, Paragraph [0019] Line 10, the phrase “See independent experiment in Fig. S5D” likely refers to a supplemental figure which has not been included in the instant specification.
On Pg. 5, Paragraph [0022] Line 3 describes Fig. 5 by stating “Genes in red in this MA plot….”. The black and white drawings submitted does not show this coloration in red (see also drawings objections). Likewise, on Pg. 6, Paragraph [0023] Fig. 6 Lines 4-6, the phrase “(B) In vitro phagocytosis assay with mouse bone marrow-derived macrophages (BMDMs) marked by immunofluorescence by F4/80 (red)….” Contains the same issue of the figure that is illustrated in red color but instant specification is in black and white only.
On Pg. 5, Paragraph [002] Line 6, the phrase “See Table S1” likely refers to a supplemental table which has not been included in the instant specification. Likewise, on Pg. 6, Paragraph [0023] Line 4, the phrase “See Table S2” presents the same issue of a missing table.
Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on Pg. 39 Paragraph [00148]: https://en.novogene.com/. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http://, www., or other browser-executable code. See MPEP § 608.01.
The use of the terms including but not limited to Yervoy (Pg. 15 Line 3), Optivo (Pg. 15 Paragraph [0061] and several other medication brand names and company names in the same paragraph), Macrogenics (Pg. 15 Paragraph [0062] and several other company names in the same paragraph), Abitrexate (Pg. 31 Paragraph [00129] and numerous other medication brand names in the same paragraph continued through to Pg. 33), Hyclone (Pg. 38 Paragraph [00142] and several other product names and company names in the same paragraph as well as on Pg. 39-41 Paragraphs [00143] to [00145] and [00147] to [00154] ), which are trade names, or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 1, 17, 19 and 20 are objected to because of the following informalities:
Claim 1 requires verbiage that makes it clear from the outset that the claimed “method for treatment of a cancer in a patient” is for a patient that has cancer.
Claim 17 recites the generic names of the drugs "Nivolumab" and "Cemiplimab" with the first letter in capital letters which should be replaced by small letters “nivolumab” and “cemiplimab”. In addition, the phrase “anti-PD-1 monoclonal antibody clone” recited before “RMP1-14” is unnecessary and can be deleted.
Claim 19 recites the phrase "…fractions of from…" which should be replaced by “…fractions of..”
Claim 19 is missing a period at the end of the sentence.
Claim 20 should be amended to recite “….selected from a group consisting of a hyperfractionation scheme and an accelerated fractionation”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-20 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a method for treating CD47+ cancer with combination therapy of radiation with a CD47 blocker, does not reasonably provide enablement for similar methods against just any cancer or for preventing cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to perform the process of the invention commensurate in scope with these claims.
The breadth of the claims is drawn to methods of treating and/or preventing cancer in a patient comprising administering to said patient an effective dose of radiation therapy in combination with administration of an effective dose of a CD47 blocking agent.
The nature of the invention includes a method of cancer treatment and/or prevention that comprises administration of therapeutic doses of radiation and a CD47 blocking agent.
The level of skill of one skilled in this art is high.
Amount of direction or guidance presented and working examples:
With regards to the treatment and prevention of cancer, on Pg. 19 Paragraph [0079], the instant specification teaches that the terms "treatment", "treating" and the like, refer to administering an agent, or carrying out a procedure, for the purposes of obtaining an effect which may be prophylactic in terms of completely or partially preventing a disease or symptom thereof. In the same paragraph, the instant specification teaches that the term "Treatment" as used herein may include preventing the disease or a symptom of a disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it.
Further on Pg. 39 of the instant specification, one finds in Paragraph [00144] that for allograft models, tumors were allowed to grow for 10-14 days. Then in Paragraph [00145] on Pg. 39, the specification teaches that for xenograft models, tumors were allowed to grow for 10-14 days. Further in Paragraph [00146] on Pg. 39, the specification teaches that for all tested treatment models, therapeutic agents were administered by intraperitoneal injection and that for all models, tumor growth was monitored by tumor dimension measurements that were used to calculate tumor volume.
Thus, the instant specification discloses methods of using radiation and a CD47 blocking agent to treat mice models that have tumors. The specification, however, does not provide methods for the prevention of tumor growth or cancers.
With regards to treatment of types of cancer using CD47 blocking agents, on Pg. 34 Paragraph [00135], the instant specification teaches that the molecule CD47 is highly expressed on the surface of SCLC cells. Also, in Paragraph [0024] on Pg. 6, the instant specification teaches in Fig. 7(B) the quantification of the expression of CD47 in KP1 cells by flow cytometry. Further in Paragraph [0045] on Pg. 11, it is taught that in some embodiments, the instant anti-CD47 agent does not directly induce cell death of a CD47-expressing cell.
Further on Pg. 13 Paragraph [0052], the instant specification teaches that cells that express higher levels of CD47 relative to other cells will be preferentially phagocytosed. Likewise in Paragraph [0053], the instant specification teaches that cells that express higher levels of CD47 relative to normal, non-target cells will be preferentially phagocytosed.
Moreover, on Pg. 36 Paragraph [00137] of the instant specification, it is further taught that as a single agent, treatment with the CD47-blocking antibody had minimal effects on tumor growth, possibly because of cross-reactivity to CD47 expressed on red blood cells and other cells in the body, with fewer molecules of antibody being able to bind to SCLC cells. In contrast, the combination treatment with radiation therapy significantly inhibited tumor growth (Fig. 1 D), which correlated with a further increase in the infiltration of macrophages (Fig. 1 E-F) (Paragraph [00137]). The specification further teaches in the same paragraph that similar experiments performed with the same mouse SCLC cell line in which the gene coding for CD47 was knocked out (Fig. 7B-C) showed that CD47 loss led to decreased tumor growth, which was further reduced by radiation therapy (Fig. 7D-E) (Paragraph [00137]).
Thus, the instant specification disclosed significant inhibition of tumor growth by using radiation and a CD47 blocking agent to treat cancers that expressed CD47, for example in SCLC.
State of the prior art, unpredictability of the art and relative skill of those in the art:
Regarding cancer prevention, no material has been found to date that has been shown to or would be expected to prevent cancer, and there is no working example, prior art, or any evidence that would provide the skilled artisan with any predictable guidance to use the claimed invention. It would be reasonable to conclude the claimed invention is not enabled.
Reasonable guidance with respect to preventing any cancer relies on quantitative analysis from defined populations that have been successfully pre-screened and are predisposed to particular types of cancer. This type of data might be derived from widespread genetic analysis, cancer clusters, or family histories. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of clinical cancer and link those results with subsequent histological confirmation of the presence or absence of disease. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent. Further, a preventive administration also must assume that the therapeutic will be safe and tolerable for anyone susceptible to the disease. The instant application has not provided in the specification any quantitative analyses nor safety data that can be taken as support for its ability to prevent cancers. Thus, prevention of cancers by the instant claimed invention is not enabled.
The vaccine art teaches that compositions comprising some tumor associated antigens are effective in treatment of cancer through generation of immunogenic response to the tumor antigen (see for example, Komenaka et al., Clinics in Dermatology, 2004, Vol. 22, Pg. 251-265, specifically page 257). However, nowhere in the art does it show that tumor antigens are effective at preventing cancer. Evans et al. (Q. J. Med 1999: 92: 299-307) teach that vaccines against cancer are not fully established, and it is stated that adjuvant therapy to prevent or delay disease still needs experimentation. Evans et al. further state that such cancer vaccines are at best used as a therapeutic and not as a prophylactic and that “the notion that cancer vaccines will replace standard therapeutic strategies in malignant disease still belongs to the realm of fiction” (see page 303 last paragraph).
In some cases, it is known that certain cancers arise from a single cause. This cause can be viral as in the case of cervical cancer, caused predominantly by persistent cervical infection with human papillomavirus (HPV) (Schiffman et al., The New England Journal of Medicine, Vo. 353, No. 20, Pg. 2101-2104, 2005). Schiffman et al. teach that primary prevention through vaccination against HPV might be possible in young women (Pg. 2101, Column 3, Paragraph, first partial). However, they also teach that vaccine evaluations are ongoing (Pg. 2103, Column 3, Paragraph, first full). In addition, the most promising vaccines designed against HPV types 16 and 18 would only prevent 70 percent of cervical cancer cases at best (Pg. 2103, Column 2, Paragraph, first full). Therefore, there is still no vaccine that can definitively prevent a cancer. Current evidence points only to the potential of future prophylactic agents.
The art of small molecule chemotherapeutics teaches that some molecules successful at treating cancers can also reduce risk. Cuzick et al. (The Lancet, Vol. 361, Pg. 296-300, 2003) teach that tamoxifen can reduce the risk of ER-positive breast cancer but cannot be recommended as a preventive agent (Pg. 299, Column 2, Paragraph, first). The reason it cannot be recommended centers around the need for continued research into specific subgroups of high-risk but healthy women for whom the risk-benefit ratio is sufficiently positive to recommend prophylactic tamoxifen treatment (Pg. 299, Column 2, Paragraph, first).
With respect to peptide-based cancer prevention agents, the art currently does not recognize a definitive example though promising candidates are present. Hernandez-Ledesma (Peptides, Vol. 30, Pg. 426-430, 2009) teaches that lunasin, a peptide discovered in soy has demonstrated cancer-preventative capacity in vitro and mouse models (Abstract). The authors define it as a perfect candidate to exert an in vivo cancer-preventive activity but more research is required to establish it in this role (Pg. 429, Column 2, Paragraph, first partial).
In view of the Wands factors discussed above, there is lack of the predictability of the art to which the invention pertains (as evidenced by prior art referenced). There is also lack of guidance and direction provided by Applicant. Undue experimentation would be required to, quantify the extent to which prevention of cancer can be attained, with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification on how to effectively practice this without disclosing the method in which prevention of cancer can be achieved with their inventive product. Working examples providing evidence which is reasonably predictive that cancer prevention can be obtainable was also absent. Therefore, in view of the state of the art, the lack of experimentation and objective evidence in the specification does not allow one skilled in the art to predict the claimed method for prevention of cancer. As such, claims 1-20 were determined to not meet the scope of enablement requirement of 35 U.S.C. 112(a) and are rejected here. This is because the prior art has only recognized the treatment of a cancer as being enabled.
Regarding treatment of just any type of cancer, it is well known in the art that cancer treatment is highly unpredictable. For instance, even though EGFR was identified in some cancers as a drug target, the in vitro (i.e., in a test tube) effectiveness of a drug in inhibiting the EGFR turned out to be a poor proxy for how effective that drug actually was in treating cancer in vivo (i.e., in the body). Numerous EGFR inhibitors that showed promising in vitro activity failed for a variety of reasons. These included poor pharmacokinetics due to poor absorption or rapid metabolism, undesirable drug-drug interactions, drug toxicity due to drug binding onto healthy cells, drug toxicity due to binding onto other receptors, and metabolite toxicity. Some drug candidates were limited by one or more of these shortcomings, further underscoring the unpredictable nature of cancer treatment. See OSI Pharmaceuticals , LLc, v. Apotex Inc, 939 F.3d 1375, 2019.
With respect to treating a patient with just any cancer, this is not enabled to its full scope since not every type of cancer will contain cancer cells that present or express CD47. This is because it is well-known in the art that cancers are made up of heterogeneous cells with varying proteomes.
Hoon (US2006/0115832, published 07/01/2006) teaches metastatic melanoma tumors are heterogeneous in melanoma marker expression (0128). Linke (US2006/0275844, published 12/07/2006) teaches that tumor tissue tends to be heterogeneous and predictive value of markers requires validation (0239). Diamandis (US2012/0178111, published 07/12/2012) teaches that lung cancer is a heterogeneous disease (0202). Pecker (US2003/0148321, published 08/07/2003) teaches CLL of B cell origin does not share the same patterns of surface expression of markers as CLL of T cell origin (0124). Thus, even CLLs are heterogeneous in surface presentation of proteins. Dalla-Favera (US2008/0280297, published 11/13/2008) teaches differential expression of markers in two groups of CLL patients (0138). Kipps (US2011/0190157, published 08/04/2011) teaches protein biomarkers differ between aggressive CLL and indolent CLL B cells (0053).
Therefore, since tumors are heterogeneous in the proteins they express/present, only cancers comprising cancer cells that present CD47 are enabled for treatment with the claimed methods. As broadly as cancer is currently claimed, the claims are not enabled to their full scope and are rejected here.
Claim Rejections - 35 USC § 102
(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, 2, 4, 7, 9, and 18 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Cui (WO2019084692A1 Date Published 2019-05-09) as evidenced by Townsend (Onco Targets Ther. 2017 Mar 30;10:1921-1932).
Cui teaches treatment of cancer that involves the use of radiation and a CD47-binding agent (Abstract). They teach that the anti-cancer effect of a CD47 blocking agent is enhanced when combined with radiation therapy (Abstract). They also teach in claim 1, a method for treating a subject presenting with CD47+ disease cells, comprising administering to the subject a treatment-effective combination of a CD47 blocking agent and radiation. They further teach in claim 13 the method wherein the CD47 blockade drug comprises an Fc fusion protein comprising the V region of soluble human SIRPa variant 2. They also further teach that in these forms the named SIRPαFc showed dramatic effects on the viability of cancer cells that present with a CD47+ phenotype (Paragraph [003]).
Cui teaches in claim 18, the method wherein the subject presents with CD47+ cancer cells that are blood cancer cells or solid tumor cells, and in claim 23, wherein the CD47+ cancer is lung cancer. They further teach in Paragraph [0087] that the in vivo efficacy of radiation therapy (RT), SIRPαFc, and RT+SIRPαFc was evaluated in subcutaneous B cell lymphoma (SUDHL-6) and solid tumor xenografts, including the radio-insensitive A549 lung adenocarcinoma (subcutaneous). As evidenced by Townsend, A549 cancer cell line is a non-small-cell lung cancer cell line (Abstract).
In Paragraph [0089], Cui teaches that the sequence of radiation therapy (RT) and SIRPαFc administration impacts the efficacy of treatment, with concurrent SIRPαFc and RT being the most effective. They teach in claim 28 that the radiation treatment comprises a fractionation dosing schedule.
With respect to the thereby clause of claim 1, it does not receive patentable weight.
The court noted (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. Here, the thereby clause only recites the intended result of the method steps recited and so receives no weight. Since Cui teaches the method steps of claim 1, it is anticipated. Furthermore, it is noted that, since the method is taught in Cui, all intended results thereof and latent properties thereof will necessarily occur.
Therefore, Cui anticipates claims 1, 2, 4, 7, 9, and 18, and these claims are thus rejected here.
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 way 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.
Claim(s) 1, 2, 4, 7, 9, 10, 15 and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Cui (WO2019084692A1 Date Published 2019-05-09) in view of Townsend (Onco Targets Ther. 2017 Mar 30;10:1921-1932), Oh (US20040097463A1, Date Published 05/20/2004), Sircar (US7375118 Date Published 05/20/2008), and Kettle (US10273227 Date Published 04/30/2019).
Cui teaches treatment of cancer that involves the use of radiation and a CD47-binding agent (Abstract). They teach that the anti-cancer effect of a CD47 blocking agent is enhanced when combined with radiation therapy (Abstract). They also teach in claim 1, a method for treating a subject presenting with CD47+ disease cells, comprising administering to the subject a treatment-effective combination of a CD47 blocking agent and radiation. They further teach in claim 13 the method wherein the CD47 blockade drug comprises an Fc fusion protein comprising the V region of soluble human SIRPa variant 2. They also further teach that in these forms the named SIRPαFc showed dramatic effects on the viability of cancer cells that present with a CD47+ phenotype (Paragraph [003]).
Cui teaches in claim 18, the method wherein the subject presents with CD47+ cancer cells that are blood cancer cells or solid tumor cells, and in claim 23, wherein the CD47+ cancer is lung cancer. They further teach in Paragraph [0087] that the in vivo efficacy of radiation therapy (RT), SIRPαFc, and RT+SIRPαFc was evaluated in subcutaneous B cell lymphoma (SUDHL-6) and solid tumor xenografts, including the radio-insensitive A549 lung adenocarcinoma (subcutaneous). As evidenced by Townsend, A549 cancer cell line is a non-small-cell lung cancer cell line (Abstract).
In Paragraph [0089], Cui teaches that the sequence of radiation therapy (RT) and SIRPαFc administration impacts the efficacy of treatment, with concurrent SIRPαFc and RT being the most effective. They teach in claim 28 that the radiation treatment comprises a fractionation dosing schedule.
Cui does not explicitly teach that the CD47 blocking agent and radiation are administered on alternating days. Nor do they teach that a series of therapeutic doses of the CD47 blocking agent are provided over the course of the radiation therapy. They also do not teach that the conventional fractionation scheme delivers up to 60 or 66 Gray (Gy) daily in fractions of from 2 to 2.75 Gy, or that the radiation therapy is delivered in a fractionation scheme selected from a hyperfractionation scheme and an accelerated fractionation.
However, Cui does provide the teachings below which make up for these deficiencies.
Cui teaches that radiation therapy can be administered within from about 1 day to about 21 days prior to and/or after administering the CD47 blocking agent (Paragraph [0069]. They also teach that the time period for treatment can be extended significantly, where several weeks (e.g., about 1, about 2, about 3, about 4, about 5, about 6, about 7, or about 8 weeks or more) lapse between the administration of the CD47 blocking agent and the radiation therapy (Paragraph [0069]).
Cui teaches in Paragraph [0054] that fractionation regimens are individualised between different radiation therapy centers and even between individual doctors such that in North America, Australia, and Europe, the typical fractionation schedule for adults is 1.8 to 2 Gy per day, five days a week. Cui also teaches that for radiotherapy, dosing levels and regimens will be determined by the type, location and stage of cancer being treated where the dose can be photon- or proton-based and expressed in Gray units to indicate the absorbed dose (Gy) of radiation and that total dosages per exposure can vary from about 1 to about 500 Gy and particularly 40-70Gy (Paragraph [0058]).
They further teach that fractionation of a dosing schedule is common, including accelerated fractionation where treatment is given in larger daily or weekly doses to reduce the number of weeks of treatment; and hyperfractionation whereby smaller doses of radiation are given more than once a day (Paragraph [0054]).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to optimize the treatment regimen including dosing schedule of CD47 blocking agent and radiation as well as the radiation fractionation scheme and dosage based on Cui teaching such parameters as described supra so as to best treat each patient. In addition, Oh at Paragraph [0035] teaches one of skill can optimize drug dose via routine experimentation; Sircar teaches a treatment regimen including frequency of dosing and duration of treatment may be determined by the skilled practitioner (Column 158, Paragraph, fourth); and Kettle teaches that where a combination therapy is administered sequentially or separately, the interval between the sequential doses may be judged by a skilled practitioner (Column 22, Paragraph, third). Thus, it is clear that all doses, intervals of dosing (such as concurrent on alternating days), sequence of administrations, and number of doses of each composition are result effective variables and can be determined by one of ordinary skill in this art with only routine experimentation. All these affect the levels of each drug in the patient overtime which in turn affects treatment efficacy.
It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980).
Thus, all said values and parameters in the instant claims are obvious.
Therefore, taken together, the combination of art above clearly renders the claimed inventions above as a whole prima facie obvious.
Claim(s) 1, 2, 4, 6, 7, 9-13, 15 and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Cui (WO2019084692A1 Date Published 2019-05-09), Townsend (Onco Targets Ther. 2017 Mar 30;10:1921-1932), Oh (US20040097463A1, Date Published 05/20/2004), Sircar (US7375118 Date Published 05/20/2008), and Kettle (US10273227 Date Published 04/30/2019), as applied to claims 1, 2, 4, 7, 9, 10, 15 and 18-20 above, and further in view of Sallman (J Clin Oncol Vol 38 (15) Suppl.7507 May 25, 2020) and Häfner (Visc Med 2016;32:172–177).
The combined teachings of Cui, Townsend, Oh, Sircar and Kettle render obvious instant claims 1, 2, 4, 7, 9, 10, 15 and 18-20 as discussed above in the first 103 which is incorporated here in its entirety.
However, they do not teach the method for treatment of a cancer wherein the cancer is a colorectal cancer. They also do not teach the method wherein the CD47 blocking agent is an antibody that specifically binds to CD47 and wherein the antibody is magrolimab.
These deficiencies are remedied by the art below.
Sallman teaches that magrolimab, also named Hu5F9-G4, is an anti-CD47 antibody that demonstrated preclinical synergy with cetuximab in refractory KRAS wild type (KRASwt) and KRAS mutant (KRASm) colorectal (CRC) tumors. Sallman also teach that the combination treatment is a novel, well-tolerated combination immunotherapeutic treatment regimen with clinical responses observed in two previously treated CRC patients and encouraging survival in KRASm patients.
However, Sallman does not teach the method for the treatment of colorectal cancer comprising administration of an effective dose of radiation therapy.
These deficiencies are remedied by the art below.
Häfner teaches that radiotherapy has been established as an essential part of perioperative concepts in advanced-stage colorectal cancer (CRC) and was introduced as an option to face challenges such as local relapse or oligometastases (Abstract). They also teach that radiotherapeutic concepts are crucial for the management of recurrent or oligometastatic CRC (Pg. 176 Column, second, Paragraph, first).
It would therefore have been obvious before the filing of the instant application to one of ordinary skill in the art to substitute the SIRPαFc CD47 blocking agent of Cui with the CD47 specific antibody magrolimab as taught by Sallman and combine it with the radiation therapy taught by Cui for cancer treatment or the radiotherapy specifically taught by Häfner for the treatment of advanced stage colorectal cancer, to arrive at the instantly claimed method for the treatment of colorectal cancer comprising administration of radiation therapy in combination with the administration of an effective dose of a CD47 blocking agent. Also, it is obvious to combine the CD47 blocking agent taught by Sallman and radiation therapy taught by Häfner for the treatment of colorectal cancer because these treatments were separately taught for the treatment of the same type of cancer, namely colorectal cancer. “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) (citations omitted). In addition, PHOSITA would enjoy a reasonable expectation of success in using the obvious method in colorectal cancer owed to the successes in the prior art of using such therapeutic methods for the treatment of colorectal cancers as discussed supra.
Taken together, the combination of art above clearly renders the claimed inventions above as a whole prima facie obvious.
Claim(s) 1, 2, 4, 6-13, 15 and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Cui (WO2019084692A1 Date Published 2019-05-09), Townsend (Onco Targets Ther. 2017 Mar 30;10:1921-1932), Oh (US20040097463A1, Date Published 05/20/2004), Sircar (US7375118 Date Published 05/20/2008), and Kettle (US10273227 Date Published 04/30/2019), Sallman (J Clin Oncol Vol 38 (15) Suppl.7507 May 25, 2020) and Häfner (Visc Med 2016;32:172–177) as applied to claims 1, 2, 4, 6, 7, 9-13, 15 and 18-20 above, and further in view of NCT03763149 (Record History 2018-12-01).
The combined teachings of Cui, Townsend, Oh, Sircar, Kettle, Sallman and Häfner render obvious instant claims 1, 2, 4, 6, 7, 9-13, 15 and 18-20 as discussed above in the second 103 which is incorporated here in its entirety.
However, they do not teach the method for treatment of a cancer wherein the cancer is metastatic.
These deficiencies are remedied by the art below.
NCT03763149 is a study which evaluated the safety, tolerability and initial efficacy of recombinant anti-CD47 monoclonal antibody IBI188 via injection in patients with advanced malignant tumors and lymphomas (Title). It teaches that one of the inclusion criteria for patients into the clinical trial was that patients were confirmed by histology or cytology for locally advanced unresectable or metastatic solid tumors and lymphomas that were refractory to standard therapy, or for which no standard therapy exists (Inclusion Criteria).
It would therefore have been obvious before the filing of the instant application to one of ordinary skill in the art to substitute the SIRPαFc CD47 blocking agent of Cui with the CD47 specific antibody IB188 as taught by NCT03763149 to arrive at the instantly claimed method for the treatment of metastatic cancer comprising administration of radiation therapy in combination with the administration of an effective dose of a CD47 blocking agent that is an antibody that specifically binds to CD47 and wherein the antibody is magrolimab. Also, PHOSITA would enjoy a reasonable expectation of success in using the obvious method in metastatic cancer owed to the successes in the prior art of using such combination therapeutic methods for the treatment of cancers as discussed supra. Of note, metastatic cancer includes stage IV disease.
Taken together, the combination of art above clearly renders the claimed inventions above as a whole prima facie obvious.
Claim(s) 1-4, 6-13, 15 and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Cui (WO2019084692A1 Date Published 2019-05-09), Townsend (Onco Targets Ther. 2017 Mar 30;10:1921-1932), Oh (US20040097463A1, Date Published 05/20/2004), Sircar (US7375118 Date Published 05/20/2008), and Kettle (US10273227 Date Published 04/30/2019), Sallman (J Clin Oncol Vol 38 (15) Suppl.7507 May 25, 2020), Häfner (Visc Med 2016;32:172–177) and NCT03763149 (Record History 2018-12-01), as applied to claims 1, 2, 4, 6-13, 15 and 18-20 above, and further in view of Weiskopf (J Clin Invest. 2016;126(7):2610-2620).
The combined teachings of Cui, Townsend, Oh, Sircar, Kettle, Sallman, Häfner and NCT03763149 render obvious instant claims 1, 2, 4, 6-13, 15 and 18-20 as discussed above in the third 103 which is incorporated here in its entirety.
However, they do not teach the method for treatment of a cancer wherein the cancer is small cell lung cancer (SCLC).
These deficiencies are remedied by the art below.
Weiskopf teaches CD47-blocking immunotherapies as a potential approach for the treatment of SCLC based on the observation that the disruption of the interaction of CD47 with SIRPα using anti-CD47 antibodies induced macrophage-mediated phagocytosis of human SCLC patient cells in culture (Abstract). They teach that the prognosis of SCLC patients is dismal, with 5-year survival rates hovering around 5% since the 1970’s and that except for the combination of radiation and chemotherapy, there have been no new therapeutic approaches implemented in the clinic in the past few decades (Pg. 2610 Column first and second, Paragraph, spanning). They also teach that in a murine model, administration of CD47-blocking antibody Hu5F9-G4, a humanized antibody that blocks the interaction between CD47 and SIRPα, markedly inhibited SCLC tumor growth (Abstract and Pg. 2614 Figure 3).
It would therefore have been obvious before the filing of the instant application to one of ordinary skill in the art to substitute the SIRPαFc CD47 blocking agent of Cui with the CD47 specific antibody Hu5F9-G4 as taught by Weiskopf (which is the same antibody taught by Sallman in the second 103), and combine that with the radiation therapy taught by Weiskopf as a previously established treatment option for SCLC, to arrive at the instantly claimed method for the treatment of SCLC comprising administration of radiation therapy in combination with the administration of an effective dose of a CD47 blocking agent. Also, since a CD47 antibody was specifically taught by Weiskopf in SCLC and radiation therapy was an established treatment modality for SCLC as taught by Weiskopf, it is therefore obvious to combine these therapies for the treatment of SCLC. “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) (citations omitted). In addition, PHOSITA would enjoy a reasonable expectation of success in using the obvious method in SCLC owed to the successes in the prior art of using such combination therapeutic methods for the treatment of cancers as discussed supra.
Taken together, the combination of art above clearly renders the claimed inventions above as a whole prima facie obvious.
Claim(s) 1-4, 6-15 and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Cui (WO2019084692A1 Date Published 2019-05-09), Townsend (Onco Targets Ther. 2017 Mar 30;10:1921-1932), Oh (US20040097463A1, Date Published 05/20/2004), Sircar (US7375118 Date Published 05/20/2008), and Kettle (US10273227 Date Published 04/30/2019), Sallman (J Clin Oncol Vol 38 (15) Suppl.7507 May 25, 2020), Häfner (Visc Med 2016;32:172–177), NCT03763149 (Record History 2018-12-01), and Weiskopf (J Clin Invest. 2016;126(7):2610-2620), as applied to claims 1-4, 6-13, 15 and 18-20 above, and further in view of NCT03783403 (Record History 2018-12-19).
The combined teachings of Cui, Townsend, Oh, Sircar, Kettle, Sallman, Häfner, NCT03763149 and Weiskopf render obvious instant claims 1-4, 6-13, 15 and 18-20 as discussed above in the fourth 103 which is incorporated here in its entirety.
However, they do not teach the method for treatment of a cancer wherein the CD47 blocking agent is an antibody that specifically binds to SIRPα.
These deficiencies are remedied by the art below.
NCT03783403 is a study to evaluate the safety and tolerability of escalating doses of CC-95251, a monoclonal antibody directed against SIRPα, in participants with advanced solid and hematologic cancer as a single agent and in combination with cetuximab and rituximab (Title and Detailed Description).
It would therefore have been obvious before the filing of the instant application to one of ordinary skill in the art to substitute the SIRPαFc CD47 blocking agent of Cui with the SIRPα specific antibody CC-95251 as taught by NCT03783403, as both are inhibitors of CD47 interaction with its ligand SIRPa, to arrive at the instantly claimed method for the treatment of cancer comprising administration of radiation therapy in combination with the administration of an effective dose of a CD47 blocking agent. Also, PHOSITA would enjoy a reasonable expectation of success in using the obvious method in the treatment of a cancer owed to the successes in the prior art of using such combination therapeutic methods for the treatment of cancers as discussed supra.
Taken together, the combination of art above clearly renders the claimed inventions above as a whole prima facie obvious.
Claim(s) 1-4, 6-20 are rejected under 35 U.S.C. 103 as being unpatentable over Cui (WO2019084692A1 Date Published 2019-05-09), Townsend (Onco Targets Ther. 2017 Mar 30;10:1921-1932), Oh (US20040097463A1, Date Published 05/20/2004), Sircar (US7375118 Date Published 05/20/2008), and Kettle (US10273227 Date Published 04/30/2019), Sallman (J Clin Oncol Vol 38 (15) Suppl.7507 May 25, 2020), Häfner (Visc Med 2016;32:172–177), NCT03763149 (Record History 2018-12-01), Weiskopf (J Clin Invest. 2016;126(7):2610-2620) and NCT03783403 (Record History 2018-12-19), as applied to claims 1-4, 6-15 and 18-20 above, and further in view of NCT02890368 (Record History 2018-01-25) and Schmidt (Semin Immunopathol 2018 Oct 29;41(1):21–30).
The combined teachings of Cui, Townsend, Oh, Sircar, Kettle, Sallman, Häfner, NCT03763149, Weiskopf and NCT03783403 render obvious instant claims 1-4, 6-15 and 18-20 as discussed above in the fifth 103 which is incorporated here in its entirety.
However, they do not teach the method for treatment of a cancer further comprising administering an effective dose of a PD-1 blocking agent in combination with the CD47 blocking agent. They also do not teach that the PD-1 blocking agent is selected from nivolumab, pidilizumab, AMP-514, pembrolizumab, AUNP 12, anti-PD-1 monoclonal antibody clone RMP1-14 or cemiplimab.
These deficiencies are remedied by the art below.
NCT02890368 is the study of TTI-621, an SIRPα-IgG1 Fc soluble recombinant fusion protein created by directly linking the sequences encoding the N-terminal CD47 binding domain of human SIRPα with the Fc domain of human immunoglobulin (IgG1), in patients that have relapsed and refractory percutaneously accessible solid tumors (Detailed Description), as a monotherapy or in combination with PD-1/PD-L1 inhibitors (Arms and Interventions). For the combination therapy study, TTI-621 was given in combination with one of the following programmed death-1 (PD-1) or programmed death-ligand-1 (PD-L1) inhibitors: nivolumab, pembrolizumab, durvalumab, avelumab, or atezolizumab administered on Day 1 (Arms and Interventions).
Of note, the SIRPαFc taught by Cui is also referred to as TTI-621 when the SIRPα component is SEQ ID NO: 2 and the SIRPαFc fusion comprises SEQ ID NO: 9 (Cui Paragraph [0037]) Thus, TTI-621 of NCT02890368 is identical to the CD47 blocking agent of SIRPαFc taught by Cui (in the 102 above and in the first 103 above).
It would therefore have been obvious before the filing of the instant application to one of ordinary skill in the art to combine the SIRPαFc CD47 blocking agent and radiation therapy of Cui with PD-1 inhibitors such as nivolumab and pembrolizumab as taught by NCT02890368 to arrive at the instantly claimed method for the treatment of cancer comprising administration of radiation therapy in combination with the administration of an effective dose of a CD47 blocking agent, further comprising administering an effective dose of nivolumab or pembrolizumab as the PD-1 blocking agent in combination with the CD47 blocking agent. The ordinary artisan would have been motivated to use the obvious combination because said combination would have resulted in a method with improved treatment efficacy by including PD-1 checkpoint inhibitors that have remarkable clinical activities in shrinking tumors across a wide range of tumor types including NSCLC and lymphoma, in causing durable responses, and in their tolerability either as a monotherapy or in combination with other agents (Schmidt Abstract, Pg. 21 Column, first, Paragraph, first, Pg. 22 Table 1 and Pg. 26 Table 2). Also, PHOSITA would enjoy a reasonable expectation of success in using the obvious combination method in the treatment of cancer owed to the successes in the prior art of using such combination therapeutic methods for the treatment of cancers as discussed supra.
Taken together, the combination of art above clearly renders the claimed inventions above as a whole prima facie obvious.
Claim(s) 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Cui (WO2019084692A1 Date Published 2019-05-09), Townsend (Onco Targets Ther. 2017 Mar 30;10:1921-1932), Oh (US20040097463A1, Date Published 05/20/2004), Sircar (US7375118 Date Published 05/20/2008), and Kettle (US10273227 Date Published 04/30/2019), Sallman (J Clin Oncol Vol 38 (15) Suppl.7507 May 25, 2020), Häfner (Visc Med 2016;32:172–177), NCT03763149 (Record History 2018-12-01), Weiskopf (J Clin Invest. 2016;126(7):2610-2620), NCT03783403 (Record History 2018-12-19), NCT02890368 (Record History 2018-01-25) and Schmidt (Semin Immunopathol 2018 Oct 29;41(1):21–30), as applied to claims 1-4, 6-20 above, and further in view of Barrera (British Journal of Cancer (2017) 117, 385–397).
The combined teachings of Cui, Townsend, Oh, Sircar, Kettle, Sallman, Häfner, NCT03763149, Weiskopf, NCT03783403, NCT02890368 and Schmidt render obvious instant claims 1-4, 6-20 as discussed above in the sixth 103 which is incorporated here in its entirety.
However, they do not teach the method for treatment of a cancer, wherein the cancer is NSCLC stage II, III, or IV.
These deficiencies are remedied by the art below.
Barrera teaches that in patients with NSCLC, there is a strong correlation between poor clinical outcomes and high neutrophil content (Pg. 386 Column, first, Paragraph, third). Barrera also teaches that CD47 expression on the surface of neutrophils is increased in NSCLC patients and was associated with a delay in neutrophil apoptosis and with an impairment in their phagocytic clearance by macrophages, suggesting that CD47 overexpression may be one of the underlying mechanisms leading to neutrophilia in the set of studied patients who had stage IIIB and IV NSCLC (Abstract and Pg. 386 Column, second, Paragraph, second “Study design”). Barrera further teaches that their results in advanced stage IIIB and IV NSCLC suggest that an advantage of CD47-blocking therapies in tumor control could be the regulation of neutrophil accumulation (Pg. 395, Column, first, Paragraph, third).
It would therefore have been obvious before the filing of the instant application to one of ordinary skill in the art to apply the method of administering SIRPαFc CD47 blocking agent and radiation therapy for the treatment of NSCLC as taught by Cui to the treatment of NSCLC stage IIIB and IV as taught by Barrera, to arrive at the instantly claimed method for the treatment of NSCLC stage II, III or IV comprising administration of radiation therapy in combination with the administration of an effective dose of a CD47 blocking agent. The ordinary artisan would have been motivated to use the obvious combination in the treatment of NSCLC stage II, III or IV because Barrera teaches that there could be an advantage from blocking CD47 in stage IIIB and IV NSCLC by affecting the neutrophil population that is correlated with poor clinical outcomes (Pg. 386 Column, first, Paragraph, third and Pg. 395, Column, first, Paragraph, third). Also, PHOSITA would enjoy a reasonable expectation of success in using the obvious combination method in the treatment of stage II, III or IV NSCLC owed to the successes in the prior art of using such combination therapeutic methods for the treatment of NSCLC as discussed supra.
Taken all together, the combination of art above clearly renders the claimed inventions above as a whole prima facie obvious.
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