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 the Application
The amendment of 7 November 2022 is entered.
Claims 1-15 are pending and are being examined on the merits.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
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 10-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of enhancing, stimulating, or increasing immune response, and blocking the interaction of PD-L1 with PD-1 and/or CD80 using the disclosed compounds, does not reasonably provide enablement for a method for inhibiting growth, proliferation, and/or metastasis of cancer cells or treating infectious disease or septic shock using the same compounds. 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.
“[T]o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.’” Genentech Inc. v. Novo Nordisk 108 F.3d 1361, 1365, 42 USPQ2d 1001, 1004 (Fed. Cir. 1997); In re Wright 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); See also Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 1212, 18 USPQ2d 1016, 1026 (Fed. Cir. 1991); In re Fisher 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Further, in In re Wands 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) the court stated:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman [230 USPQ 546, 547 (BdPatAppInt 1986)]. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredict-ability of the art, and (8) the breadth of the claims.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
The Nature of the Invention
Claims 10-11 are drawn to methods of inhibiting growth, proliferation or metastasis of cancer cells using compounds of Formula I. Claims 12-13 are drawn to methods of treating infectious diseases using compounds of Formula I. Claim 14 is drawn to methods of treating septic shock using compounds of Formula I.
The breadth of the claims
The scope of the claims with respect to cancer is extremely broad and includes all cancer and tumor types. Claim 11, which is the narrowest in scope, includes several different cancers including melanoma, renal cell carcinoma, squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, colorectal cancer, castration-resistant prostate cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, squamous cell carcinoma of the head and neck, carcinomas of the esophagus, gastrointestinal tract and breast, and hematological malignancies
The scope of the claims with respect to infectious diseases is extremely broad and includes all viral, bacterial and fungal infections. Claim 13, which is the narrowest in scope, includes all viral infections.
The scope of the claims with respect to septic shock is also broad as it encompasses shock resulting from any cause.
The State of the Prior Art
The Examiner is not aware of prior art disclosing compounds of Formula I.
The prior art suggests that PD-1 pathway inhibitors are promising therapies for a variety of cancers. In a review article published the year of the earliest effective filing date of the instant application, Dolan et al. (Cancer Control, July 2014, Vol. 21, No. 3 pp. 231-237) state:
The PD-1/PD-L1 pathway in cancer is implicated in tumors escaping immune destruction and is a promising therapeutic target. The development of anti–PD-1 and anti–PD-L1 agents marks a new era in the treatment of cancer with immunotherapies. Early clinical experience has shown encouraging activity of these agents in a variety of tumors, and further results are eagerly awaited from completed and ongoing studies.
However, the prior art fails to disclose small molecule PD-1 pathway inhibitors that treat cancer.
The Predictability or Unpredictability of the Art
The prior art pertaining to the development of small molecule inhibitors of the PD-1/PD-L1 interaction is highly unpredictable. Barakat (J. Pharm. Care & Health Systems 1:e119) teaches on p. 1000e:
Despite all these advantages over current immune checkpoint’s antibodies, very limited efforts have been directed to development of small molecules toward these targets. This is mainly due to the limited structural information on these proteins. For example, current PD-1 crystal structures describe PPIs of mouse PD-1 and human PD-L1 or with mouse PD-L2. Similarly, there is only one structure for the mouse TIM-3. Lacking the detailed human protein-protein interactions is a barrier to rationally design small molecule inhibitors for these targets.
In addition, the art is highly unpredictable with respect to the treatment of infectious diseases using PD-1 inhibitors. In a post-filing date review, Wykes et al. (Nature Reviews Immunology, 2018, Vol 18, pp. 91-104) acknowledge the development of anti-PD-1 antibodies for cancer and note the relative lack of validation of this pathway as a target for infectious diseases (p. 91, last paragraph):
Whether immunotherapies can also be effective for treating infectious diseases is less well explored. However, the fact that these inhibitory pathways are also exploited for immune evasion by pathogens suggests that their blockade could be used for the prevention and treatment of infectious diseases, in either the acute or chronic phases of infection.
In addition, the art is highly unpredictable with respect to the treatment septic shock using PD-1 inhibitors. In a post-filing date publication, Busch et al. (Intensive Care Medicine Experimental, 2020, Vol. 8, No. 7, pp. 1-19) report a disconnect between promising preclinical data and clinical results (p. 2, paragraph 2):
Checkpoint molecule expression is reportedly increased in septic patients, and there has been interest in using CPIs to augment host defense for sepsis due to acute bacterial infection. This therapeutic approach has risks though, since CPIs could elicit host inflammation and aggravate sepsis-associated inflammatory injury. Despite such risks, CPIs have been reported to improve bacterial clearance and survival in several animal bacterial sepsis models. Based in part on these preclinical studies, two phase I clinical trials have been conducted testing CPI therapy in patients presenting with severe sepsis or septic shock. However in one, treatment with an anti-PD-L1 mAb did not have apparent benefit, and a planned phase II trial was not conducted. A second phase I sepsis trial of an anti-PD-1 mAb was completed in January 2018, but further clinical trials have not been announced.
The Relative Skill of Those in the Art
The relative skill in the art is high, although it is not within the ordinary skill in the art to use small molecule inhibitors of the PD-1 and PD-L1 interaction to inhibit cancer or treat infectious disease or septic shock.
Level of Guidance in the Specification
The specification does not include guidance that establishes the PD-1/PD-L1 inhibitors as inhibitors of cancer cell growth.
The specification does not include guidance that establishes the PD-1/PD-L1 interaction as a validated target for the treatment of infectious disease or septic shock.
The Presence or Absence of Working Examples
The specification does not provide any working examples specific to inhibiting cancer cells or treating infectious diseases or septic shock.
The Quantity of Experimentation Necessary
Considering the factors above, the skilled artisan would be burdened with undue experimentation in determining if one of the claimed compounds would be effective at inhibiting cancer cells or treating an infectious disease or septic shock. Absent any guidance from the art and specification, the skilled artisan would be burdened with testing a broad range of compounds in an attempt to discover which ones can be used for the claimed purpose.
In view of the Wands factors as discussed above, it is the Examiner’s opinion that the claims are not fully enabled and one of skill in the art would have to engage in undue experimentation to practice the invention as claimed herein, without a reasonable assurance of success.
Claims 9-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for methods of using compounds of formula (I) where R9 is OH, does not reasonably provide enablement for compounds of formula (I) where R9 is H or C1-3 alkyl. 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.
“[T]o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.’” Genentech Inc. v. Novo Nordisk 108 F.3d 1361, 1365, 42 USPQ2d 1001, 1004 (Fed. Cir. 1997); In re Wright 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); See also Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 1212, 18 USPQ2d 1016, 1026 (Fed. Cir. 1991); In re Fisher 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Further, in In re Wands 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) the court stated:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman [230 USPQ 546, 547 (BdPatAppInt 1986)]. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredict-ability of the art, and (8) the breadth of the claims.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Nature of the Invention
The claims are drawn to compounds of formula (I) and their use, where formula (I) is a generic structure offering three variable positions: Rx and Ry, independently H, CH2R1, or C3-6 cycloalkyl optionally substituted with 0-5 R2a, where at least one of Rx and Ry is other than H; and R9 being H or C1-3 alkyl.
Breadth of the Claims
The claims are broad considering the Rx, Ry, and R9 substituents and possible options at each position. The methods of treatment claims are also broad in that they encompass entire conditions or cells to be impacted, i.e. inflammation, all cancer cells, any type of infectious disease, septic shock in general, or the interaction between PD-L1 and PD-1 and/or CD80.
State of the Prior Art
The Examiner is not aware of any compounds of formula (I) where R9 is OH combined with the other claimed Rx and Ry substituents.
The prior art pertaining to the development of small molecule inhibitors of the PD-1/PD-L1 interaction is highly unpredictable. Barakat (J. Pharm. Care & Health Systems 1:e119) teaches on p. 1000e:
Despite all these advantages over current immune checkpoint’s antibodies, very limited efforts have been directed to development of small molecules toward these targets. This is mainly due to the limited structural information on these proteins. For example, current PD-1 crystal structures describe PPIs of mouse PD-1 and human PD-L1 or with mouse PD-L2. Similarly, there is only one structure for the mouse TIM-3. Lacking the detailed human protein-protein interactions is a barrier to rationally design small molecule inhibitors for these targets.
In addition, the art is highly unpredictable with respect to the treatment of infectious diseases using PD-1 inhibitors. In a post-filing date review, Wykes et al. (Nature Reviews Immunology, 2018, Vol 18, pp. 91-104) acknowledge the development of anti-PD-1 antibodies for cancer and note the relative lack of validation of this pathway as a target for infectious diseases (p. 91, last paragraph):
Whether immunotherapies can also be effective for treating infectious diseases is less well explored. However, the fact that these inhibitory pathways are also exploited for immune evasion by pathogens suggests that their blockade could be used for the prevention and treatment of infectious diseases, in either the acute or chronic phases of infection.
In addition, the art is highly unpredictable with respect to the treatment septic shock using PD-1 inhibitors. In a post-filing date publication, Busch et al. (Intensive Care Medicine Experimental, 2020, Vol. 8, No. 7, pp. 1-19) report a disconnect between promising preclinical data and clinical results (p. 2, paragraph 2):
Checkpoint molecule expression is reportedly increased in septic patients, and there has been interest in using CPIs to augment host defense for sepsis due to acute bacterial infection. This therapeutic approach has risks though, since CPIs could elicit host inflammation and aggravate sepsis-associated inflammatory injury. Despite such risks, CPIs have been reported to improve bacterial clearance and survival in several animal bacterial sepsis models. Based in part on these preclinical studies, two phase I clinical trials have been conducted testing CPI therapy in patients presenting with severe sepsis or septic shock. However in one, treatment with an anti-PD-L1 mAb did not have apparent benefit, and a planned phase II trial was not conducted. A second phase I sepsis trial of an anti-PD-1 mAb was completed in January 2018, but further clinical trials have not been announced.
Relative Skill of those in the Art
The relative skill of those in the art is high.
Predictability or Unpredictability of the Art
There is a general lack of predictability in the pharmaceutical art. In re Fisher, 427, F. 2d 833, 166, USPQ 18 (CCPA 1970).
The Examples show a number of specific compounds tested for an IC50 value for PD-1/PD-L1 binding ranging from 1.4 µM to 0.0007 µM depending on Rx and Ry, not even considering any R9 being other than OH. The range of IC50 indicates a level of unpredictability in determining the impact of a given R group on the resulting molecule.
Amount of Direction or Guidance Given
There is no guidance given on using compounds where R9 is not OH. There is no guidance on the ability of other R groups to serve as immune system enhancers, cancer cell proliferation inhibitors, infectious disease treatment agents, or septic shock treatment agents.
Presence/Absence of Working Examples
Any and all working examples are such that R9 is always OH. There are no disclosed species where R9 is H or C1-3 alkyl.
No working examples show any use of compounds to inhibit cancer cells, treat infectious disease, or treat septic shock. No examples show inhibiting inflammation with compounds where R9 is anything other than OH. No examples show blocking of the interaction of PD-L1 with PD-1 and/or CD80 with compounds where R9 is H or C1-3 alkyl, as all examples are where R9 is OH.
Quantity of Experimentation Necessary
Considering the factors above, the skilled artisan would be burdened with undue experimentation in determining if one of the claimed compounds would be effective at inhibiting cancer cells or treating an infectious disease or septic shock when R9 is anything other than OH. Absent any guidance from the art and specification, the skilled artisan would be burdened with testing a broad range of compounds in an attempt to discover which ones can be used for the claimed purpose.
In view of the Wands factors as discussed above, it is the Examiner’s opinion that the claims are not fully enabled and one of skill in the art would have to engage in undue experimentation to practice the invention as claimed herein, without a reasonable assurance of success.
Allowable Subject Matter
Claims 1-8 are allowed.
The following is an examiner’s statement of reasons for allowance: The prior art fails to recognize the compounds of formula (I) where Rx and Ry are independently H, CH2R1, or C3-6 cycloalkyl and one of Rx and Ry is not H. Related immunomodulators are claimed in USP 9,856,292, but these differ in overall structure from formula (I) and does not suggest or lead one of ordinary skill in the art to the compounds as now claimed. The specific compounds of claim 8 are similarly free of the prior art as there is no art suggesting those specific side groups found at the equivalent Rx and Ry positions as found in the generic compound of formula (I). The claimed compounds are novel and unobvious.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY J MIKNIS whose telephone number is (571)272-7008. The examiner can normally be reached M-F 9-5.
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/ZACHARY J MIKNIS/Patent Examiner, Art Unit 1658