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 .
Priority
This application was filed on 03/06/2020 and claims the benefit of the priority of US Provisional application 62/815,917 filed on 03/08/2019.
Information Disclosure Statement
The information disclosure statements submitted on 08/10/2025 has been considered by the examiner.
Claim Status
Claims 1, 5-6 and 17-19 are being examined on the merits in this office action.
Claim Objections - Withdrawn
The objection of claims 1, and 17 is withdrawn in view of the claim amendments.
Claim Rejections - 35 USC § 112 - Maintained
Claims 1, 5-6, and 17-19 remain 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 a method of reducing Treg cells in breast cancer subjects and for the treatment other cancer types such advanced melanoma and renal carcinoma, the method comprising administering a cyclic iRGD peptide and aldesleukin, does not reasonably provide enablement for a method for reducing all tumors and cancers generally. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1561 (Fed. Cir., 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558,1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547, the court recited eight factors to consider when assessing whether or not a disclosure would require undue experimentation. These factors are:
1) the quantity of experimentation necessary
2) the amount of direction or guidance provided
3) the presence or absence of working examples
4) the nature of the invention
5) the state of the art
6) the relative skill of those in the art
7) the predictability of the art
8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099,1108,427 F.2d 833, 839,166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The breadth of the claims and the nature of the invention
The invention is drawn to a method of reducing the volume of a tumor in a subject or patient comprising administering a cyclic iRGD peptide and aldesleukin as recited in claim 1. The invention is also drawn to a method of treating cancer in a patient in need thereof, comprising administering a cyclic iRGD peptide and aldesleukin as recited in claim 17. Thus the instant invention recites a method of reducing the volume of any tumor, both benign and malignant and a method of treating cancer generally.
Cancer is a broad term and encompasses cancers occurring in various hard and soft tissues. The main categories include: Carcinoma (cancers that begin in the skin or tissues that line or cover organs), Sarcoma (Cancers in bone, cartilage, muscles or connective tissues), Leukemia (Cancers that form in the blood forming tissues), Lymphoma and myeloma (Cancers that begin in the immune system) and Central nervous system cancer (cancers of the brain or spinal cord). The claims of the instant application do not limit the cancer being treated, or the tumor being reduced to any particular type of cancer, for example lung cancer or breast cancer.
The instant specification is bereft of evidence of reducing any tumors including cancerous tumors and cancers in general. The specification does not demonstrate the efficacy of the combination treatment of iRGD and IL-2 in treating cancer in general and reducing all tumors including cancerous tumors. Since absolute success in treating and reducing all tumors generally is not reasonably possible based on the state of the art at the earliest effective filing date of the instant application, the specification, which lacks an objective showing that tumors such a cancerous tumors and all cancers can be actually treated or reduced, is viewed as lacking.
The claims are thus broad insofar as to suggest that the claimed method can reduce all tumors including cancerous tumors and can treat all cancers generally.
The state of the prior art and the level of predictability in the art and the relative skill of those in the art
The state of the art is such that there is evidence and established literature on the many types of cancers (National Cancer Institute-https://www.cancer.gov/about-cancer/understanding/what-is-cancer (NCI), page 6, paragraph 1- cited and enclosed in the previous office action) and each cancer has its own causative factor and different cellular behaviors (National Cancer Institute, https://www.cancer.gov/about-cancer/causes-prevention/patient-prevention-overview-pdq (NCI2) page 2 and 3- cited and enclosed in the previous office action). Examples of the numerous forms of cancers include Breast cancer, uterine corpus endometrial carcinoma, Bladder Urothelial carcinoma, Lung cancer, cervical cancer, pancreatic cancer, Prostate cancer, ovarian cancer, Blood cancer or Brain and nervous system cancers. These are further subdivided to include carcinomas like Basal cell carcinoma, squamous cell carcinoma, renal cell carcinoma and Adenocarcinoma. There are also other forms of malignant melanoma, cylindroma, germ cell tumors and many more. Treatment of cancer is complex and usually takes into consideration the type of cancer including location, its stage and genetic characteristics. Therefore treatment for one type of cancer, may not be useful in treating other types of cancers (Merck Manual - Cancer treatment Principles By Robert Gale, page 1, paragraph 1 and 2- cited and enclosed in the previous office action).
Given that there is no evidence in the art of a compound that has been found to generally treat all cancers or reduce all tumors generally including cancerous tumors, the treatment of cancer generally or reduction of all tumors is not considered enabled. Most cancer drugs are known to be effective against a limited or closely related cancers (Merck Manual - Cancer therapy, By Robert Gale, page 1, and paragraph 1, 2- cited and enclosed in the previous office action). Therefore a compound that is effective against cancer or cancerous tumors generally would be an exception and more proof of the claimed invention would be required. Merck teaches the median 5-year survival rates of various types of cancer as shown below (Merck - cancer therapy, page 3).
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Medical News Today (https://www.medicalnewstoday.com/articles/322700 - By Christina Chun- cited and enclosed in the previous office action) teaches that a 5- year survival rate does not indicate whether or not treatment has removed all signs of cancer, but is useful for comparing relative severity of different types of cancer (Medical News Today, Page 1, paragraph 8).
One of ordinary skill in the art would not be able to use the claimed invention to treat cancer and/or reduce all tumors generally and achieve a reasonable level of success in doing so due to the absence in the art of a compound that is able to treat cancer generally or reduce all tumors including cancerous tumors generally. It is well established that a utility rejection is therefore proper when the scope of enablement is not reasonably correlated to the scope of the claim.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)”. The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.”
The instant specification discloses that female mice were inoculated with 4T1 tumor cells and treated with iRGD and IL-2 and that the mice showed significant decrease in Treg cell count (Example 1).
With regards to cancer, Ex parte Kranz, 19 USPQ2d 1216, 1219 notes the “general unpredictability of the field [of] ... anti-cancer treatment.” In re Application of Hozumi et al., 226 USPQ 353 notes the “fact that the art of cancer chemotherapy is highly unpredictable”. It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved” and physiological activity is generally considered to be an unpredictable factor.
See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.).
As a result, the specification needs to have more details on how to make and/or use the invention in order to be enabling.
The relative skill of those in the art is high. However, the art of cancer treatment or reducing tumors generally is highly unpredictable.
The examiner cites EP2445536B1-cited and enclosed in the previous office action, Sausville et al. (Cancer Research, 2006, vol. 66, pages 3351-3354- cited and enclosed in the previous office action), and Johnson et al. (British J. of Cancer, 2001, 84(10):1424-1431- cited and enclosed in the previous office action) as evidentiary references to illustrate the state of the art.
EP2445536B1 teaches methods of treating human pancreatic, prostate and breast cancer model comprising administering iRGD and cancer therapeutic agent such as IL-2 [0432-0442]. The teachings of EP2445536B1 do not disclose that the method treated all cancers or all tumors generally.
Sausville et al. teach that there is insufficient predictive power of the traditionally explored tumor model systems for how actual human beings will respond to the treatment in the clinic which is in contrast to other disease areas where it translates into clinically active agents (Page 3351, column 1, line 22). Sausville et al. further teach that even when drugs with evidence of anticancer activity in preclinical in vivo models are given at their maximum tolerated doses, they frequently fail to produce useful activity in humans (Page 3351, column 1, line 28).
Johnson et al. teach that in vivo activity in a particular histology in a tumor model did not closely correlate with activity in the same human cancer histology, casting doubt on the correspondence of the pre-clinical models to clinical results (Abstract, line 4).
These teachings show how unpredictable the treatment of cancer is generally, especially in the case of a method that is used to treat or reduce cancers or tumors in general. In light of the state of the prior art, it is apparent that the instantly claimed method is not capable of use to treat all cancers and/or reduce all tumors generally.
The amount of direction or guidance provided and the presence or absence of working examples
The invention is drawn to a method of reducing the volume of a tumor in a subject or patient comprising administering a cyclic iRGD peptide and aldesleukin. The invention is drawn to a method of treating cancer in a patient in need thereof, comprising administering a cyclic iRGD peptide and aldesleukin.
The instant Example discloses that female mice were inoculated with 4T1 tumor cells and treated with iRGD and IL-2 and that the mice showed significant decrease in Treg cell count. The instant specification does not include other examples showing effect of the claimed method to reduce all tumors, and to treat all cancers generally such as brain cancer and also including all the cancers recited in instant claim 18.
The quantity of experimentation necessary
Given the well-known unpredictability of the art as well the incomplete experimental evidence commensurate in scope with the claims, the skilled artisan would not be able to agree that the claimed method can treat any and all cancers or all tumors including cancerous tumors. In order to determine if the claimed method would treat any particular cancer, the suitable dosage as well as clinical trials or assays that can correlate to clinical efficacy of such treatment would be needed. This is undue experimentation given the limited guidance and experimentation provided by the applicant.
In view of the Wands factors discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in unduly burdensome experimentation to assess whether the claimed method would be successful in treating cancers in general or reduce all tumors including cancerous tumors. Thus, the rejection of these claims under 35 USC 112(a) is proper.
Response to Arguments
Applicant's arguments filed 07/24/2025 have been fully considered but they are not persuasive.
Applicant Arguments
Applicant argues that the use of iRGD and a low cumulative dose of Aldesleukin to cause favorable changes in the immune microenvironment (lower Treg cells, CD8 T cells) transcends individual tumor types, such that the claims should not be limited to only breast cancer.
Examiner’s Response
The arguments presented above have been fully considered but are unpersuasive. Examiner notes that Applicant has not established that the instant method of administering iRGD and IL-2 at an unspecified low dose is effective to reduce any and all types of tumors. The instant specification is bereft of evidence of treating. The specification does not demonstrate the efficacy of the combination treatment of iRGD and IL-2 in treating cancer in general. Since absolute success in treating cancers or tumors is not reasonably possible based on the state of the art at the earliest effective filing date of the instant application, the specification, which lacks an objective showing that tumors such a cancerous tumors and all cancers can be actually treated, is viewed as lacking. Further, Tang et al. (Tang et al. (Cytokine X. 2018 Dec 10;1(1):100001 - reference cited to rebut Applicant’s argument) teaches that IL-2 is effective for metastatic renal cell carcinoma and metastatic melanoma and that IL-2 efficacy is limited to only certain patient subpopulations and cancer types. Examiner notes that IL-2 is effective to a specific types of cancers and patient population.
The instant Example discloses that female mice were inoculated with 4T1 tumor cells and treated with iRGD and IL-2 and that the mice showed significant decrease in Treg cell count. The instant specification does not include other examples showing effect of the claimed method to reduce all tumors, and to treat all cancers generally such as brain cancer and also including all the cancers recited in instant claim 18. The arguments are unpersuasive.
Claim Rejections - 35 USC § 103 - maintained
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.
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.
Claims 1, 5-6, and 17-19 remain rejected under 35 U.S.C. 103 as being unpatentable over EP 2445536 B1 (hereinafter “the ‘536 patent” – cited and enclosed in the previous office action) in view of Sugahara et al. in (Science 328(5981): 1031–1035, 2010 – cited and enclosed in the previous office action) and of WO 2018089669 A2 (hereinafter “the ‘669 publication” – cited and enclosed in the previous office action).
‘536 teaches a method of treating a tumor comprising administering a peptide with the sequence RPAR, CRGDK, RPARPAR or CRGD[K/R]GP[D/E]C which corresponds to the iRGD peptide (Claim 1 and paragraph ([0015-0016]), that the peptide can be circular (cyclic) [0058, 0313, 0373, 0419, 0424]. ‘536 further teaches that the peptide is co-administered with a composition that comprises a cancer chemotherapeutic agent such as a cytokine (Claims 1-3 and para. [0041]). ‘536 further discloses that the therapeutic agent may be interleukin-2 (IL-2) [0327]. ‘536 further teaches that that the use of peptides in combination with drugs such as cytokines ensures that the drug is delivered to cells and tissues of interest at higher concentrations than is possible in standard therapy and that the dose or amount of drug or other compound can be reduced without compromising the efficacy of the treatment (p. 18, line 38-39, line 45-47, paragraph [0101]). This reads on administration of the cancer chemotherapeutic agent such as a cytokine, at low doses. Furthermore, ‘536 teaches that the low doses of the drug make it possible to reduce side effects while achieving the same level of anti-tumor activity as with conventional treatment and thus, possible to revive drugs that have been previously rejected because of toxicity (p. 73, line 43-45 and paragraph [0431]). The disclosures therefore teach the instant method of co-administering IRGD with a cytokine such as IL-2 and further suggests administering the therapeutic agent such as IL-2 at a low dose rendering obvious the instant claims. Furthermore, it is known in the art that when iRGD is administered in combination with a cancer therapeutic agent, the dose of the cancer therapeutic agent can be lowered (see Sugahara et al.). Sugahara discloses that a tumor-penetrating peptide, iRGD, when administered in combination with an anti-cancer drug, such as, Doxorubicin (Dox), the combination therapy that included 1 mg/kg DOX was as potent as 3 mg/kg DOX alone, a dose that reaches the cumulative maximum tolerated dose (MTD) (Fig. 3C). Combining iRGD with 3 mg/kg of DOX potentiated the activity of DOX, inducing nearly complete tumor growth inhibition (Fig. 2C) (p. 3, 2nd paragraph, line 1-10). Sugahara further discloses that in comparison to drug administered alone, the iRGD combination therapy provides equivalent or better anti-tumor efficacy at a 3-fold lower dose of the drug, with a commensurate reduction in toxicity (p. 3, 3rd paragraph, line 5-8). Therefore, Sugahara teaches that when IRDG is co-administered with a cancer therapeutic agent, the dose of the therapeutic agent can be lower. The Examiner notes that the Sugahara reference was used for the teaching that when co-administering iRGD with a cancer therapeutic agent, the dose of the cancer therapeutic agent can be lowered significantly. Therefore, the teachings of Sugahara align with the teachings of ‘536. The only difference between the two references is that the cancer therapeutic agent is different. Examiner further notes that the ‘536 reference does not explicitly disclose by how many folds the dose is lowered, but generally teaches that the dose of the cancer therapeutic agent is significantly lowered.
With regards to the recitation that the IL-2 is aldesleukin as recited in claim 4, ‘669 teaches a method of treating cancer comprising administering an agonist that comprises aldesleukin, that the method inhibits regulatory T cells (claims 3-14), and that the method comprises administering low doses of aldesleukin or modified aldesleukin at the doses are 0.2 mg/kg [0030, 00109, 00132, 00134]. Examiner notes that such low dosages that reduce Treg are already known in the art as taught by ‘669. Examiner further notes that the reference teaches both modified and unmodified IL-2 (Aldesleukin). Therefore, the limitation of “wherein the IL-2 is unmodified recombinant IL-2 is met.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of ‘536 and Sugahara and ‘402 and prepare a method treating a tumor that comprises co-administering an IRGD peptide with a cancer therapeutic agent such as IL-2 at low dose as taught by ‘536 and suggested by Sugahara because ‘536 teaches that the dose or amount of cancer drug or other compound such as IL-2 can be reduced without compromising the efficacy of the treatment (p. 18, line 38-39, line 45-47, paragraph [0101]). While ‘536 suggests that the dose may be reduced, the reference does not disclose by how much the dose is reduced and neither do the instant claims recite a dose amount. However, one of ordinary skill in the art would be motivated to modify ‘536 and use the low dosages of IL-2 (aldesleukin) taught by ‘669. The dosages taught by ‘669 would read on the instant dose that is 50-1000-fold lower because it decreases the level of Treg cells. Furthermore, it would have been obvious to one of ordinary skill in the art to use low cumulative dose of IL-2 that are 50-1000-fold lower because the concentration of the active agent is a result effective variable and the determination of the optimum or workable ranges of said variable may be characterized by routine experimentation (See MPEP 2144 II). It would be obvious and routine experimentation to a person of ordinary skill in the art with a reasonable expectation of success to optimize the dosages to arrive at the low dosage recited in the instant claims.
Additionally and/or alternatively, MPEP 2112-2112.02 states that when a reference discloses all the limitations of a claim except for a property or function, and the examiner cannot determine whether or not the reference inherently possesses properties which anticipate or render obvious the claimed invention but has basis for shifting the burden of proof to applicant as in In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980). The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not the effective dose is 50-1000-fold lower given that none of the claims recite the actual dose being used in the instant method. The instant claims only need that aldesleukin is administered at a low dose.
One of ordinary skill in the art would be motivated and would have had a reasonable expectation of success in combining the teachings of ‘536, Sugahara and ‘669 because Sugahara teaches that the low drug doses were effective and, also led to reduction in toxicity (p. 3, 3rd paragraph, line 5-8) and ‘669 teaches that the low IL-2 doses led to inhibition of Treg (claim 4). Therefore, these low dosages that decrease Treg are known in the art and one of ordinary skill would modify ‘536 with ‘669. In addition, the limitation of decreasing Treg cells is an intended result. The MPEP 2111.04 states: claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. In the instant case, the limitations of “decreasing Treg cells” expresses the intended result of the method of claim 1 and is given little patentable weight. Furthermore, since prior art teaches the instant method, the expected result of “decreasing the level of Treg cells” is necessarily present. In addition, MPEP 2112.02(II) states that “the court upheld the rejection and stated that the applicants had merely found a new property of the compound and such a discovery did not constitute a new use. In the instant case, the limitation of “decreasing the level of Treg cells” does not constitute something new, since the instant method was known in the art.
Regarding claim 5, ‘536 teaches that the administration of the iRGD and cytokine maybe co-administered (at the same time and by the same or different route/means/form), separate administration (parallel administration by the same or different route/means/form) or sequential administration (at different times by the same or different route/means/form) (p. 48 line 43-47, [0262]).
Regarding claim 6, ‘536 teaches that the mice were intravenously injected with the composition (p. 13, line 5-6, line 14-16).
Regarding claim 17 and 18, ‘536 teaches a method of treating a tumor or cancer comprising administering a peptide with the sequence RPAR, CRGDK, RPARPAR or CRGD[K/R]GP[D/E]C which corresponds to the iRGD peptide (Claim 1 and paragraph ([0015-0016]). ‘536 further teaches that the peptide is co administered with a composition that comprises a cancer chemotherapeutic agent such as a cytokine (Claim 1-3 and para. [0041]). ‘536 further teaches that the composition was used in mice bearing orthotopic xenografts of human breast cancer (Figure 1 and 10). ‘536 further teaches that that the use of peptides in combination with drugs such as cytokines ensures that the drug is delivered to cells and tissues of interest at higher concentrations than is possible in standard therapy and that the dose or amount of drug or other compound can be reduced without compromising the efficacy of the treatment (p. 18, line 38-39, line 45-47, paragraph [0101]). This reads on administration of the cancer chemotherapeutic agent such as a cytokine, at low doses. Furthermore, ‘536 teaches that the low doses of the drug make it possible to reduce side effects while achieving the same level of anti-tumor activity as with conventional treatment and thus, possible to revive drugs that have been previously rejected because of toxicity (p. 73, line 43-45 and paragraph [0431]). ‘536 teaches that human prostate cancer, pancreatic or breast cancer xenografts were used [0082]. Examiner further notes that one of ordinary who has read both ‘536 and ‘669 would be motivated to modify ‘536 and use the low dosages of ‘669 which fall within the range of 50-1000-fold lower than what is administered in standard therapy (see [0030, 00109, 00132, 00134]. In addition, it would have been obvious to one of ordinary skill in the art to use low cumulative dose of IL-2 that are 50 to 1000-fold lower because the concentration of the active agent is a result effective variable and the determination of the optimum or workable ranges of said variable may be characterized by routine experimentation (See MPEP 2144 II). It would be obvious and routine experimentation to a person of ordinary skill in the art with a reasonable expectation of success to optimize the dosages to arrive at the dosages of the instant claims.
Regarding claim 19, ‘669 teaches a method that comprises administering low doses of aldesleukin or modified aldesleukin at the doses are 0.2 mg/kg [0030, 00109, 00132, 00134]. One of ordinary who has read both ‘536 and ‘669 would be motivated to modify ‘536 and use the low dosages of ‘669 which fall within the range of 50-1000-fold lower than what is administered in standard therapy (see [0030, 00109, 00132, 00134]. Further, Sugahara discloses that in comparison to anti-cancer drug administered alone, the iRGD combination therapy provides equivalent or better anti-tumor efficacy at a 3-fold lower dose of the anti-cancer drug, with a commensurate reduction in toxicity (p. 3, 3rd paragraph, line 5-8).
In addition, it would have been obvious to one of ordinary skill in the art to use low cumulative dose of IL-2 that are 50 to 1000-fold lower because the concentration of the active agent is a result effective variable and the determination of the optimum or workable ranges of said variable may be characterized by routine experimentation (See MPEP 2144 II). It would be obvious and routine experimentation to a person of ordinary skill in the art with a reasonable expectation of success to optimize the dosages to arrive at the dosages of the instant claims.
Claims 1, 5-6, and 17-19 remain rejected under 35 U.S.C. 103 as being unpatentable over EP 2445536 B1 (hereinafter “the ‘536 patent” – cited and enclosed in the previous office action) in view of Sugahara et al. in (Science 328(5981): 1031–1035, 2010 – cited and enclosed in the previous office action) and of WO 2012123381 A1 (hereinafter “the ‘381 publication” – cited and enclosed in the previous office action).
‘536 teaches a method of treating a tumor comprising administering a peptide with the sequence RPAR, CRGDK, RPARPAR or CRGD[K/R]GP[D/E]C which corresponds to the iRGD peptide (Claim 1 and paragraph ([0015-0016]). ‘536 further teaches that the peptide is co-administered with a composition that comprises a cancer chemotherapeutic agent such as a cytokine (Claims 1-3 and para. [0041]). ‘536 further discloses that the therapeutic agent may be interleukin-2 (IL-2) [0327]. ‘536 does not teach that the IL-2 was modified. Therefore meets the limitation that the IL-2 is unmodified. ‘536 further teaches that that the use of peptides in combination with drugs such as cytokines ensures that the drug is delivered to cells and tissues of interest at higher concentrations than is possible in standard therapy and that the dose or amount of drug or other compound can be reduced without compromising the efficacy of the treatment (p. 18, line 38-39, line 45-47, paragraph [0101]). This reads on administration of the cancer chemotherapeutic agent such as a cytokine, at low doses. Furthermore, ‘536 teaches that the low doses of the drug make it possible to reduce side effects while achieving the same level of anti-tumor activity as with conventional treatment and thus, possible to revive drugs that have been previously rejected because of toxicity (p. 73, line 43-45 and paragraph [0431]). The disclosures therefore teach the instant method of co-administering IRGD with a cytokine such as IL-2 and further suggests administering the therapeutic agent such as IL-2 at a low dose rendering obvious the instant claims. Furthermore, it is known in the art that when iRGD is administered in combination with a cancer therapeutic agent, the dose of the cancer therapeutic agent can be lowered (see Sugahara et al.). Sugahara discloses that a tumor-penetrating peptide, iRGD, when administered in combination with an anti-cancer drug, such as, Doxorubicin (Dox), the combination therapy that included 1 mg/kg DOX was as potent as 3 mg/kg DOX alone, a dose that reaches the cumulative maximum tolerated dose (MTD) (Fig. 3C). Combining iRGD with 3 mg/kg of DOX potentiated the activity of DOX, inducing nearly complete tumor growth inhibition (Fig. 2C) (p. 3, 2nd paragraph, line 1-10). Sugahara further discloses that in comparison to drug administered alone, the iRGD combination therapy provides equivalent or better anti-tumor efficacy at a 3-fold lower dose of the drug, with a commensurate reduction in toxicity (p. 3, 3rd paragraph, line 5-8). Therefore, Sugahara teaches that when IRDG is co-administered with a cancer therapeutic agent, the dose of the therapeutic agent can be lower. The Examiner notes that the Sugahara reference was used for the teaching that when co-administering iRGD with a cancer therapeutic agent, the dose of the cancer therapeutic agent can be lowered significantly. The teachings of Sugahara align with the teachings of ‘536. The only difference is that the cancer therapeutic agent is different. Examiner further notes that the ‘536 reference does not explicitly disclose by how many folds the dose is lowered, but generally teaches that the dose of the cancer therapeutic agent is significantly lowered.
With regards to the specific limitation that the IL-2 is aldesleukin as recited in claim 4, ‘381 teaches a method of treatment that comprises administering IL-2 at a dose of about 0.05 to 2MIU/day and the whole reference shows that the IL-2 is unmodified (claim 2). ‘318 teaches that IL-2 has been used in cancer treatment (Page 1, line 16-17). ‘318 teaches that the amount increases the level of Treg cells (therefore does not decrease Treg) (Page 2, line 20-30). The dose disclosed by ‘318 read on the instant low dose that is 50-1000-fold lower because the instant claims recite that such a dose of IL-2 when administered alone does not decrease the level of Treg cells. Furthermore, Examiner notes that since the instant claims do not recite the specific low dose that is about 50-1000-fold lower, Examiner looked into the instant disclosure to determine the specific dose and the disclosure on Table 1, lists such a dose as being 660,000 IU/day. ‘381 teaches that the dose is about 0.05 to 2MIU/day (claim 2) wherein the lower limit is 50,000 IU/day which falls within the dose of the instant invention. Such low dosages of IL-2 are known in the art as taught by ‘381. ‘381 further teaches that the IL-2 is Proleukin or Aldesleukin (Page 11, line 10-12).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of ‘536, Sugahara and ‘381 and prepare a method treating a tumor that comprises co-administering an IRGD peptide with IL-2 at low dose as taught by ‘536 and suggested by Sugahara and specifically use the low dosages of ‘381 because ‘536 teaches that the dose or amount of cancer drug or other compound such as IL-2 can be reduced without compromising the efficacy of the treatment (p. 18, line 38-39, line 45-47, paragraph [0101]). While ‘536 suggests that the dose may be reduced, the reference does not disclose by how much the dose is reduced and neither do the instant claims recite a dose amount. However, such low dosages are known in the art as taught by ‘381. One of ordinary skill in the art would be motivated to modify ‘536 with the low dose of ‘381 and would achieve a reasonable expectation of success.
One of ordinary skill in the art would be motivated and would have had a reasonable expectation of success in combining the teachings of ‘536, Sugahara and ‘381 because Sugahara teaches that a cancer therapeutic can be administered at low dosages when combined with iRGD and that the low drug doses were effective and, also led to reduction in toxicity (p. 3, 3rd paragraph, line 5-8). With regards to the limitation of decreasing Treg cells, the limitations recite an intended result. The MPEP 2111.04 states: claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. In the instant case, the limitations of “decreasing Treg cells” expresses the intended result of the method of claim 1 and is given little patentable weight. Furthermore, since prior art teaches the instant method, i.e. teaches the instant co-administration of IRGD and IL-2, to treat the instant patient population, at the instant dosages (i.e. dose of IL-2 wherein when administered alone increases Treg), the expected result of “decreasing the level of Treg cells” is necessarily present. In addition, MPEP 2112.02(II) states that “the court upheld the rejection and stated that the applicants had merely found a new property of the compound and such a discovery did not constitute a new use. In the instant case, the limitation of “decreasing the level of Treg cells” does not constitute something new, since the instant method was known in the art.
Regarding claim 5, ‘536 teaches that the administration of the iRGD and cytokine maybe co-administered (at the same time and by the same or different route/means/form), separate administration (parallel administration by the same or different route/means/form) or sequential administration (at different times by the same or different route/means/form) (p. 48 line 43-47, [0262]).
Regarding claim 6, ‘536 teaches that the mice were intravenously injected with the composition (p. 13, line 5-6, line 14-16).
Regarding claims 17 - 19, ‘536 teaches a method of treating a tumor or cancer comprising administering a peptide with the sequence RPAR, CRGDK, RPARPAR or CRGD[K/R]GP[D/E]C which corresponds to the iRGD peptide (Claim 1 and paragraph ([0015-0016]). ‘536 further teaches that the peptide is co administered with a composition that comprises a cancer chemotherapeutic agent such as a cytokine (Claim 1-3 and para. [0041]). ‘536 further teaches that the composition was used in mice bearing orthotopic xenografts of human breast cancer (Figure 1 and 10). ‘536 further teaches that that the use of peptides in combination with drugs such as cytokines ensures that the drug is delivered to cells and tissues of interest at higher concentrations than is possible in standard therapy and that the dose or amount of drug or other compound can be reduced without compromising the efficacy of the treatment (p. 18, line 38-39, line 45-47, paragraph [0101]). This reads on administration of the cancer chemotherapeutic agent such as a cytokine, at low doses. Furthermore, ‘536 teaches that the low doses of the drug make it possible to reduce side effects while achieving the same level of anti-tumor activity as with conventional treatment and thus, possible to revive drugs that have been previously rejected because of toxicity (p. 73, line 43-45 and paragraph [0431]). ‘536 teaches that human prostate cancer, pancreatic or breast cancer xenografts were used [0082]. In addition, ‘381 teaches a method of treatment that comprises administering IL-2 at a dose of about 0.05 to 2MIU/day (claim 2). ‘318 teaches that the amount increases the level of Treg cells (therefore does not decrease Treg) (Page 2, line 20-30). The dose disclosed by ‘318 read on the instant low dose that is 50-1000-fold lower because the instant claims recite that such a dose of IL-2 when administered alone does not decrease the level of Treg cells. Furthermore, Examiner notes that since the instant claims do not recite the specific low dose that is about 50-1000-fold lower, Examiner looked into the instant disclosure to determine the specific dose and the disclosure on Table 1, lists such a dose as being 660,000 IU/day. ‘381 teaches that the dose is about 0.05 to 2MIU/day (claim 2) wherein the lower limit is 50,000 IU/day which falls within the dose of the instant invention. One of ordinary skill in the art would be motivated to modify ‘536 and use the low dosages of ‘381 and would achieve a reasonable expectation of success.
Response to Arguments
Applicant's arguments filed 07/24/2025 have been fully considered but they are not persuasive.
Applicant Arguments
Applicant argues that Sugahara and '669 or '381 does not describe the innovation in this application that the activity of low-dose IL-2, which is immunosuppressive and would be harmful in cancer, is converted to the opposite immunostimulatory activity, which otherwise requires a dose that is 50 times, or more, higher than the low dose. Applicant argues that Sugahara et al. teaches a 3-fold difference between the doses given with and without iRGD. This is vastly different than the 50-fold or greater difference we have achieved with IL-2. Moreover, there is no existing example, in the '536 reference taken alone or in combination with Sugahara and '669 or '3 81, of the activity of the compound having been converted to the opposite (immunosuppressive to immunostimulatory) by including iRGD.
Applicant argues that the extensive effort by the pharmaceutical industry to develop a non-toxic variant of IL-2 shows that Applicant's invention addresses a major long-felt need in cancer therapy.
Examiner’s Response
The arguments presented above have been fully considered but are unpersuasive. Examiner notes the instant invention is drawn to a method of treating, inhibiting, or reducing the volume of a tumor in a subject comprising administering iRGD and low dose of IL-2 (aldesleukin). The ‘536 reference teaches a method of treating a tumor comprising administering a peptide with the sequence RPAR, CRGDK, RPARPAR or CRGD[K/R]GP[D/E]C which corresponds to the iRGD peptide (Claim 1 and paragraph ([0015-0016]), that the peptide can be circular (cyclic) [0058, 0313, 0373, 0419, 0424], that the peptide is co-administered with a composition that comprises a cancer chemotherapeutic agent such as a cytokine (Claims 1-3 and para. [0041]) and that the therapeutic agent may be interleukin-2 (IL-2) [0327]. The instant invention only requires that the IL-2 is administered at a low dose, which the ‘536 reference teaches. Examiner notes that such a method of treating tumors or cancer using a combination of the iRGD peptide and a cancer therapeutic agent is known in the art. Specifically, it is known that when a cancer therapeutic agent is administered in combination with the peptide, the cancer therapeutic agent is administered at significantly lower dosages. This is taught by both ‘536 and the Sugahara reference. The Examiner notes that the Sugahara reference was used to disclose the similarity with the ‘536 reference, specifically that when co-administering iRGD with a cancer therapeutic agent, the dose of the cancer therapeutic agent can be lowered significantly.
Regarding Applicant argument about “immunostimulatory activity”, Examiner notes that the ‘669 teaches combination treatment with IL-2 and teaches that IL-2 is administered at low dosages that reduce Treg cells. ‘669 further teaches that method stimulated the immune system. Applicant argument regarding the instant invention having “immunostimulatory activity” is unpersuasive.
Further, since the instant claims do not recite the actual low dosage of IL-2, and only recite that the combination with low dose IL-2 decreases the level of Treg cells, Examiner looked into the instant disclosure to determine the specific dose and the disclosure on Table 1, lists such a dose as being 660,000 IU/day. Examiner notes that the ‘669 reference teaches ‘669 teaches a method of treating cancer comprising administering an agonist that comprises aldesleukin, that the method inhibits regulatory T cells (claims 3-14), and that the method comprises administering low doses of aldesleukin or modified aldesleukin at the doses are 0.2 mg/kg [0030, 00109, 00132, 00134]. Examiner notes that such low dosages that reduce Treg are already known in the art as taught by ‘669. Applicants’ argument that ‘669 does not teach or suggest using low dose IL-2 alone is unpersuasive, since the instant invention similarly teaches combination therapy. Further, the reference was used to teach low dosages of IL-2 that are disclosed in the instant specification. These are the same low dosages in the instant invention and are known to decrease Treg cells.
Examiner further insists that the limitation of “..Treg cells…” constitute an intended result. The Examiner notes that the instant method has been rendered obvious by the cited references. Specifically, ‘536 teaches the method treating that comprises administering a combination or iRGD peptide and IL-2, and further that the IL-2 can be administered at a lower dose. Even though the reference does not expressly disclose the dose, the reference teaches that the dose is lower than what is administered in standard therapy. One of ordinary skill in the art, through routine experimentation, would be able to arrive at dosages low dosages.
Furthermore, the MPEP 2112.02(II) states that “the court upheld the rejection and stated that the applicants had merely found a new property of the compound and such a discovery did not constitute a new use. In the instant case, the limitation of “decreasing the level of Treg cells” does not constitute something new, since the instant method was known in the art. In addition, such low cumulative dosages were already known to used successfully in the art as disclosed above. The Examiner asserts that the low dosages are therefore not a new use since such low dosages have been used successfully by prior art. One of ordinary skill in the art would be motivated to administer IL-2 at lower dosages as suggested by ‘536 such as the ones disclosed by ‘669, ‘381, and WO2001/003718A2 (Reference previously used to rebut Applicant’s arguments – and enclosed in the previous office action). Since combination treatments comprising iRGD and IL-2 are known in the art and such low IL-2 dosages are known in the art, the results of decreasing the level of Treg cells would be necessarily present. The Examiner further cites WO 2017/190684A1 (Reference previously used to rebut Applicant’s arguments– and enclosed in the previous office action) that teaches combination therapy with iRGD and IL-2 for treatment a malignant tumor (see claims 1-2, and Example 10). The instant method of treatment is known in the art. MPEP 2145(II) states that the “[m]ere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention.” In re Baxter Travenol Labs., 952 F.2d 388 (Fed. Cir. 1991). "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Further, Examiner disagrees with Applicant’s argument of a long-felt need for the treatment of additional cancers using IL-2. Examiner insists that low IL-2 has been used for the treatment of tumors as disclosed in the rejections and arguments above. Further, WO2001/003718A2 (Reference previously used to rebut Applicant’s arguments– and enclosed in the previous office action) teaches the use IL-2 for tumor treatment and teaches dosages such as those disclosed in the instant specification (600,000 IU). Further WO 2017/190684A1 (Reference previously used to rebut Applicant’s arguments – and enclosed in the previous office action) teaches combination therapy with iRGD and IL-2 for treatment a malignant tumor (see claims 1-2, and Example 10) and teaches low dosages.
Examiner notes that combination therapy with iRGD and IL-2 for treatment a malignant tumors was already known in the art as stated above in the claim rejection and response to arguments. As stated earlier in the claim rejection, this need was already being met. In addition, establishing a long-felt need requires objective evidence that an art recognized problem existed in the art for a long period of time without solution. The relevance of a long-felt need and the failure of others to the issue of obviousness depends on several factors. First, the need must have been a persistent one that was recognized by those of ordinary skill in the art. See MPEP 716.04. In the instant case, combination therapy with iRGD and IL-2 for treatment cancer was taught by the primary reference ‘536 and further teaches that the cancer drug is administered at a lower dose in such a combination. Sugahara discloses similar teachings. Furthermore, ‘669 teaches the specific low dosages disclosed in the instant specification and that such dosages did not decrease Treg cells when administered alone. Therefore, the need of using IL-2 for cancer therapy was known in the art and already used by others. According to the MPEP 716.04 (I), the long-felt need must not have been satisfied by another before the invention by applicant. This argument is therefore unpersuasive.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mercy H. Sabila whose t