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 .
Claim of Foreign Priority
Applicant’s claim of foreign priority to Application GB 2107825.8 and Certified Foreign Priority documents have been received by the Office.
Status of the Claims
Claims 1-3, 5-19, 21, and 23 are pending and examined.
Information Disclosure Statement
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. This includes those references listed on pages 7, 14, and 29, among others, of the Specification.
Claim Rejections - 35 USC § 112
Claims 5 and 6 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 5 includes a preamble that lists 6 conditions. However, the body of the claim indicates that the patient is suffering from 5 conditions. It is not clear how a subject with pneumonia can be treated if they do not have pneumonia. Clarification is requested.
Claim 6 refers to “ageusia (loss of taste).” However, ageusia means a complete loss of taste. If the term ageusia is synonymous with the language in the parenthesis, the phrase in the parenthesis is superfluous. Alternatively, if it is intended to mean a partial loss of taste, e.g., is included, it is modifying the accepted definition in the art of the condition. Clarification is requested.
Claim Rejections – 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(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 1-3, 5-16, 18, and 23 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 mitigation of symptoms relating to a coronavirus, does not reasonably provide enablement for treatment of all forms of pneumonia, anosmia, ageusia, and/or chronic cough, which is interpreted by the examiner to include one of these symptoms of any etiology with spironolactone monotherapy at any dosage. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to treat pneumonia, anosmia, ageusia, and/or chronic cough secondary to any condition, including COPD, asthma, lung cancer, and anosmia or ageusia as an adverse event to chemotherapy toxicity. Further, the Specification defines the term treatment to include prevention. In particular, paragraph 33 of the Specification defines treating and variations of treating to include preventing symptoms, inhibiting the disorder “that may be afflicted with or predisposed to the condition….” This is interpreted to include those subjects that do not yet have a condition.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.”
In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are:
1. The nature of the invention
2. The state of the prior art
3. The predictability or lack thereof in the art
4. The amount of direction or guidance present
5. The presence or absence of working examples
6. The breadth of the claims
7. The quantity of experimentation needed, and
8. The level of skill in the art
The Nature of the Invention
Claims 1-3, 5-16, 18, and 23 are drawn to treating and preventing symptoms that are not restricted to those caused by a coronavirus infection. Treatment and prevention of the claimed conditions/symptoms includes treating a subject that has or is capable of having, e.g., chronic cough caused by asthma, COPD, interstitial pulmonary fibrosis, lung cancer, e.g. Further, as noted below, loss of senses, including sense of smell and/or taste is a common side effect of chemotherapy. Thus, the invention includes treating and preventing the same.
The State of the Prior Art and the Predictability or lack thereof in the art
The state of the prior art is that the pharmacological art involves screening invitro and in vivo to determine which compounds exhibit the desired pharmacological activities (i.e. what compounds can treat which specific diseases/conditions by what mechanism). There is no absolute predictability even in view of the seemingly high level of skill in the art. The existence of these obstacles establishes that the contemporary knowledge in the art would prevent and treat one of ordinary skill in the art from accepting any therapeutic regimen on its face.
The instantly claimed invention is highly unpredictable as discussed below: It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the instantly claimed invention is highly unpredictable since one skilled in the art would recognize that the underlying pathology is broad.
The Amount of Direction / Guidance Present and the Presence or Absence of Working Examples
The examples in the Specification begin on page 23. In each of Studies 1 and 2, all patients were confirmed to have COVID-19. Similarly, spironolactone was administered at 100 mg/day in both studies. Further, a combination therapy with dexamethasone at 4 mg/day was most effective in recovery of taste, smell, cough, and fever. See Spec. @ par. 168. There is no example of prevention.
The working examples are focuses solely on symptoms that are being treated that are caused by, and are secondary to, COVID-19. Patients in Example 1 were treated with DEX and spironolactone. See par. 147. A focus of the Specification’s working examples is combination therapy with DEX and spironolactone in subjects with COVID-19.
The level of the skill in the art
The level of skill in the art is high. However, due to the unpredictability in the pharmaceutical art as described above, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro and in vivo screening to determine whether the compound exhibits the desired pharmacological activity. The amount of guidance or direction needed to enable the invention is inversely related to the degree of predictability in the art. In re Fisher, 839, 166 USPQ 24. Thus, although a single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements, in cases involving unpredictable factors, such as most chemical reactions and physiological activity, more teaching or guidance is required. In re Fishcher, 427 F.2d 839, 166 USPQ 24; Ex Parte Hitzeman, 9 USPQ 2d 1823.
The quantity of experimentation needed
The quantity of experimentation needed is undue experimentation. One of skill in the art would need to definitively determine the specific population of individuals who would need to be treated and would furthermore have to determine which conditions that cause a claimed symptoms are treatable with a claimed agent. To treat all forms and causes of chronic cough, anosmia, ageusia, and others, would require undue experimentation to both develop an animal model which would reasonably correlate with all forms of the claimed symptoms.
The examiner was not able to locate any support that spironolactone can treat chronic cough caused by lung cancer, COPD, asthma, and conditions; and
The examiner was not able to locate any support that spironolactone can treat chemotherapy-induced anosmia and ageusia, e.g.
As evidenced by: Drareni et al., “Loss of smell in lung cancer patients undergoing chemotherapy: Prevalence and relationship with food habit changes,” Lung Cancer, Volume 177, March 2023, 29-36, it is known that cancer patients undergoing cytotoxic chemotherapies exhibit a series of adverse side effects including modifications in smell and taste perception. See p1, line 1.
“Cancer patients undergoing cytotoxic chemotherapies exhibit a series of adverse side effects including smell and taste alterations, which can have a significant impact on their food behavior and quality of life.”
Thus, factors such as “sufficient working examples”, “the level of skill in the art” and “predictability”, etc. have been demonstrated to be sufficiently lacking in the instantly claimed methods. In view of the breadth of claim 5, the chemical nature of the invention, and the lack of working examples regarding the activity of the claimed compounds, one having ordinary skill in the art would have to undergo an undue amount of experimentation to use the invention commensurate in scope with the claims.
The court in Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001, states that, “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.”
Therefore, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation to test which diseases can be treated or prevented by the compound encompassed in the instant claims, with no assurance of success.
In view of no working examples, Applicant must rely on that which is already known in the art to enable the methods of treatment and prevention, as well as the subject populations described therein.
The examiner did not extend this rejection to the breadth of mineralcorticoid receptor antagonists, generally, in view of the small genus of compounds comprised therein and their recognized activity in the art. Further, while treatment may be provided for in certain contexts within the Specification and prior art, there is no basis of record that prevention is enabled.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 8-11, 15-19, and 21 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Prendergast, (US2009/0053294).
Prendergast teaches a method of treating and/or preventing a viral infection in a subject by administering an antimineralcorticoid compound including spironolactone, eplerenone, or eplerenone. See prior art claims 67 and 73. Further, the viral infection can be a coronavirus. See prior art claim 80. Further, the composition can be administered orally or nasally. See prior art claim 82. The composition can be administered as a nasal inhalation or spray. See par. 75. Treatment is intended to ameliorate one or more symptoms associated with a viral infection. See par. 22. Antimineralcorticoid dosages will range from 5 to 500 mg/day and ideally 400 mg/day. See par. 82. Tablets, capsules, liquids, solids, troches, lozenges, melts, inhalations, and others forms can be used. See par. 65.
As such, claims 1-3, 8-11, 15-19, and 21 are anticipated by the prior art.
Claims 1-3, 5-13, 15, 17, 18, 21, and 23 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Javid et al., (US20200330487) (filed July 3, 2020).
Javid teaches treating and preventing SARS-coronaviruses with spironolactone. See Abstract. This includes SARS-Covid-19 and provides for symptomatic relief. See par.’s 3, 4, 7-9. An effective amount of spironolactone includes about 25-50 mg. See par. 12. Administration can be oral or nasal. See par. 18. Treatment includes reducing viral load and providing symptomatic relief. See par. 32. Symptoms are known to include pneumonia, among others. See par. 4. Spironolactone can be administered from about 1-3.3 mg/kg/day orally. See par. 41. It can be administered in a dose of 25 mg orally twice daily. It can also be increased to 2-3 times daily if needed. This is a total of 25 mg to 75 mg daily. See par. 42. Pharmaceutically acceptable carriers and excipients are contemplated for use. See par.’s 49, 50, and others.
As such, claims 1-3, 5-13, 15, 17, 18, 21, and 23 are anticipated by the prior art.
Claims 1-3, 8-12, 18, and 21are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Henry, (US20210346403) (filed May 7, 2021).
Henry teaches treating Covid-19 by administering eplerenone and spironolactone. Spironolactone can be administered in a range of 25 mg to 100 mg. See Abstract. Severe symptoms are taught to be treatable. See par. 10. See claim 1 and 7 below.
1. A use of a compound that targets mineralocorticoid receptors to treat coronavirus disease 2019 (COVID-19).
7. A method for treating a patient with a compound that targets mineralocorticoid receptors, wherein the patient is suffering from coronavirus disease 2019 (COVID-19), the method comprising the steps of: determining whether the patient has the COVID-19 by obtaining a biological sample from the patient; and, if the patient has the COVID-19, administering the compound.
As such, claims 1-3, 8-12, 18, and 21 are anticipated by the prior art.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-3, 5-19, 21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Javid et al., (US20200330487) (filed July 3, 2020), in view of Prendergast, (US2009/0053294).
Javid teaches treating and preventing SARS-coronaviruses with spironolactone. See Abstract. This includes SARS-Covid-19 and provides for symptomatic relief. See par.’s 3, 4, 7-9. An effective amount of spironolactone includes about 25-50 mg. See par. 12. Administration can be oral or nasal. See par. 18. Treatment includes reducing viral load and providing symptomatic relief. See par. 32. Symptoms are known to include pneumonia, among others. See par. 4. Spironolactone can be administered from about 1-3.3 mg/kg/day orally. See par. 41. It can be administered in a dose of 25 mg orally twice daily. It can also be increased to 2-3 times daily if needed. This is a total of 25 mg to 75 mg daily. See par. 42. Pharmaceutically acceptable carriers and excipients are contemplated for use. See par.’s 49, 50, and others.
Prendergast also teaches a method of treating and/or preventing a viral infection in a subject by administering an antimineralcorticoid compound including spironolactone, eplerenone, or eplerenone. See prior art claims 67 and 73. Further, the viral infection can be a coronavirus. See prior art claim 80. Further, the composition can be administered orally or nasally. See prior art claim 82. The composition can be administered as a nasal inhalation or spray. See par. 75. Treatment is intended to ameliorate one or more symptoms associated with a viral infection. See par. 22. Antimineralcorticoid dosages will range from 5 to 500 mg/day and ideally 400 mg/day. See par. 82. Tablets, capsules, liquids, solids, troches, lozenges, melts, inhalations, and others forms can be used. See par. 65.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985); and Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
It would have been prima facie obvious to a person having ordinary skill in the art prior to the filing of the instant application to combine the teachings of Javid and Prendergast to arrive at the claimed product and methods. One would be motivated to do so because Javid and Prendergast each teach treating viral infections including SARS Covid-19 infection by administering spironolactone nasally and/or orally to treat and prevent the same. Further, such administration is taught to treat pneumonia. Moreover, the dosages taught to be efficacious include ranges that fall within and overlap the claimed ranges. As such, a POSA would be able to optimize such dosage through nothing more than routine experimentation. Even further, symptomatic relief is taught and symptoms are known to include pneumonia among others. As such, there is a reasonable and predictable expectation of success in arriving at the claimed methods in view of the teachings of the cited prior art.
With further regard to claim 23, a loading dose is common for rapidly achieving therapeutic efficacy of claimed API. Further, claim 23 allows for a dose of 50 mg-100 mg followed by a maintenance dose that is also 50-100 mg. The optimization of a known result effective API through a known mechanism of action is obvious to a person of ordinary skill in the art.
Claims 1-3, 5-19, 21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Javid et al., (US20200330487) (filed July 3, 2020), in view of Prendergast, (US2009/0053294), and in view of Cadegiani et al., “Spironolactone: An Anti-androgenic and Anti-hypertensive Drug That May Provide Protection Against the Novel Coronavirus (SARS-CoV-2) Induced Acute Respiratory Distress Syndrome (ARDS) in COVID-19,” Front Med, 27 July 2020.
Javid teaches treating and preventing SARS-coronaviruses with spironolactone. See Abstract. This includes SARS-Covid-19 and provides for symptomatic relief. See par.’s 3, 4, 7-9. An effective amount of spironolactone includes about 25-50 mg. See par. 12. Administration can be oral or nasal. See par. 18. Treatment includes reducing viral load and providing symptomatic relief. See par. 32. Symptoms are known to include pneumonia, among others. See par. 4. Spironolactone can be administered from about 1-3.3 mg/kg/day orally. See par. 41. It can be administered in a dose of 25 mg orally twice daily. It can also be increased to 2-3 times daily if needed. This is a total of 25 mg to 75 mg daily. See par. 42. Pharmaceutically acceptable carriers and excipients are contemplated for use. See par.’s 49, 50, and others.
Prendergast also teaches a method of treating and/or preventing a viral infection in a subject by administering an antimineralcorticoid compound including spironolactone, eplerenone, or eplerenone. See prior art claims 67 and 73. Further, the viral infection can be a coronavirus. See prior art claim 80. Further, the composition can be administered orally or nasally. See prior art claim 82. The composition can be administered as a nasal inhalation or spray. See par. 75. Treatment is intended to ameliorate one or more symptoms associated with a viral infection. See par. 22. Antimineralcorticoid dosages will range from 5 to 500 mg/day and ideally 400 mg/day. See par. 82. Tablets, capsules, liquids, solids, troches, lozenges, melts, inhalations, and others forms can be used. See par. 65.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985); and Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Further, Cadegiani teaches a study in which spironolactone was used as an API for treating COVID-19. See p2, 1st full par. The most prevalent symptoms were anosmia (71.1%), ageusia (67.0%). See p2, 2nd full par. The group administered spironolactone was significantly less likely to be asymptomatic and spironolactone mitigated additional risks associated with hyperandrogenic (HA) phenotype. See p3, 1st par. Antiandrogens were shown to be a plausible treatment when used chronically to improve outcomes in COVID-19. See p5, 3rd full par. In the study, anosmia and ageusia were almost absent in the spironolactone users. See p19, 1st par.
It would have been prima facie obvious to a person having ordinary skill in the art prior to the filing of the instant application to combine the teachings of Javid, Prendergast, and Cadegiani to arrive at the claimed product and methods. One would be motivated to do so because Javid and Prendergast each teach treating viral infections including SARS Covid-19 infection by administering spironolactone nasally and/or orally to treat and prevent the same. Further, such administration is taught to treat pneumonia. Moreover, the dosages taught to be efficacious include ranges that fall within and overlap the claimed ranges. As such, a POSA would be able to optimize such dosage through nothing more than routine experimentation. Even further, symptomatic relief is taught and symptoms are known to include pneumonia among others. As such, there is a reasonable and predictable expectation of success in arriving at the claimed methods in view of the teachings of the cited prior art. Even further, Cadegiani teaches a specific subject population that has Covid-19 and anosmia by administration of spironolactone, which are additional risks associated with hyperandrogenic phenotype. Antiandrogens were shown to be a plausible treatment when used chronically to improve outcomes in COVID-19 and in the study, anosmia and ageusia were almost absent in the spironolactone users.
With further regard to claim 23, a loading dose is common for rapidly achieving therapeutic efficacy of claimed API. Further, claim 23 allows for a dose of 50 mg-100 mg followed by a maintenance dose that is also 50-100 mg. The optimization of a known result effective API through a known mechanism of action is obvious to a person of ordinary skill in the art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D BARSKY whose telephone number is (571)272-2795. The examiner can normally be reached on 9-5 M-F.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628