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 .
DETAILED ACTION
Claim 1-14 and 16-19 are pending and are under consideration in the instant office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/02/2023 and 12/05/202 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits. See attached copy of the PTO-1449.
Priority
This application is a National Stage (371) of PCT/GB2022/050836, filed April 1, 2022, which claims priority to GB 2104742.8, filed April 1, 2021, and GB 2107026.3, filed May 17, 2021
Claim Objections
Claim 12 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 112
The following is a quotation of the second paragraph of 35 U.S.C. 112:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 16-19 are rejected under 35 U.S.C. 112, second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claims 16-19 are vague and indefinite in that the recitation of “treating SARS-CoV-2” is awkward and does not really make sense since virus cannot obviously be treated . SARS-CoV-2 is the actual virus, while the disease caused by SARS-CoV-2 which is COVID 19 is the condition which can be treated. Appropriate correction is recommended. For the purposes of this examination these claims are interpreted as being drawn to a method of treating COVID19.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 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 16-19 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. 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.
In evaluating the enablement question, several factors are to be considered. Note In re Wands, 8 USPQ2d 1400 and Ex parte Forman, 230 USPQ 546. The factors include: 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, and 7) the quantity of experimentation needed.
1-2) The nature of the invention and Breadth of the claims:
The instant claims 16-19 are drawn to a method of treating SARS-CoV-2 in a subject in need thereof comprising administering an effective therapeutic amount of a compound of formula 1b shown below with the variables as defined in the claim or with the pharmaceutical composition comprising the same.
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Scope of the compounds covered:
The instant claims are drawn to compounds of generic formula (1b) shown below, all of which are claimed to be useful for the method of treating SARS-CoV-2 in a subject.
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The formula contains 5 different R groups which include aryl, heteroaryl, heterocycloalkyl, heterocycloalkyl, cycloalkyl, etc.
As such the compounds of the claim encompass molecules that widely vary in the physical and chemical properties such as size, molecular weight, acidity, basicity, and properties that are known in the art to greatly influence pharmacokinetic and pharmacodynamics parameters, not to mention the ability to productively bind to claimed biological target molecules. The claims cover compounds easily in the hundreds given the number of possible rings, ring systems and substitutions covered by the claims' scope along with varying choices for remaining variables.
Scope of the disease covered:
Applicants are claiming treatment of SARS-CoV-2 which is being interpreted as being as claiming treatment of COVID-19. As taught by Wiersinga et al. (JAMA 2020,:324(8); 782-793), COVID-19 has various clinical manifestation, including respiratory failure, septic shock and/or multiple organ failure. Patients can present with gastrointestinal symptoms, olfactory and gustatory dysfunction , anosmia or ageusia. Complications include impaired function of the heart, brain, lung, liver, kidney and coagulation system, COVID-19 can lead to myocarditis, cardiomyopathy ventricular arrythmias, and hemodynamic instability. Acute cerebrovascular disease and encephalitis are observed in certain patients. Venous and thromboembolic evens occur in many patients with COVID-19 (page 786, col.2, para 2-5).
3-4) The state of the prior art and unpredictability in the art :
The state of the prior art is such that it involves screening both in vitro and in vivo to determine which compounds exhibit the desired pharmacological activities (i.e. which compounds treat which specific amyloid associated disease). 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 one of ordinary skill in the art from accepting any therapeutic regimen on its face.
As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.” As discussed above, the instantly claimed invention pertains to compounds of Formula (Ib), which are alleged by the Specification to act as agents which are used to treat COVID-19. At the time the instant application was filed, it would have been known by those of ordinary skill in the art that due in large part to the strict requirement of complementarity between a compound and its corresponding binding site on a target receptor or enzyme - compounds, in the vast majority of cases, demonstrate a remarkably high correlation between their structure, specificity and ability to produce a pharmacological effect. At the same time, it would have also been generally assumed that two compounds with similar chemical properties would exhibit similar biological effects. Thus, given a series of compounds that are shown to exert an activity of interest (or given a target of interest), the ordinarily skilled artisan would have expected that a limited genus of related compounds (e.g., compounds exhibiting near equal molecular shapes and volumes, approximately the same distribution of electrons, and similar physical properties such as hydrophobicity, etc.) would interact with the given target to elicit a related biological response.
As stated in MPEP 2164.01(c), “[w]hen a compound or composition claim is limited by a particular use, enablement of that claim should be evaluated based on that limitation”. Thus, as stated in MPEP 2164.08, “[t]he focus of the examination inquiry is whether everything within the scope of the claim is enabled” (emphasis added). Indeed, 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 (Fed. Cir. 1993) (emphasis added).
At the same time, however, it is also recognized that not everything necessary to practice the invention need be disclosed. Nor is it necessary that an Applicant test all the embodiments of his invention. In re Angstadt, 537 F.2d 498 (CCPA 1976) (emphasis added). In fact, as stated by the court in In re Buchner, 929 F.2d 660 (Fed. Cir. 1991), a patent need not teach, and preferably omits, what is well known in the art.
Accordingly, for purposes of enablement, the relevant concern is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate in scope with the protection sought by the claims. Thus, while a patent application is entitled to claim his invention generically” it is necessary that “he provide a disclosure sufficient to enable one skilled in the art to carry our the invention commensurate with the scope of his claims". Amgen, In.c, v. Chugai Pharmaceutical Co., Ltd. (Fed. Cir. 1991). As noted by the court in In re Fisher, 427 F.2d 833 (CCPA 1970), the scope of enablement must bear a “reasonable correlation” to the scope of the claims. See also Ak Steel Corp. v. Sollac, 344 F.3d 1234 (Fed. Cir. 2003) and In re Moore, 439 F.2d 1232 (CCPA 1971). As stated in MPEP 2164.08, resolution of this concern requires two stages of inquiry: “[t]he first is to determine how broad the claim is with respect to the disclosure. The entire claim must be considered. The second inquiry is to determine if one skilled in the art is enabled to make and use the entire scope of the claim without undue experimentation”.
Applicants recite the ability of these compounds to treat COVID0-19 based on their ability to inhibit Mpro active sites on SARA-CoV-2 virus. The various disorders associated with COVID-19 while it is due to the viral infection, has various different pathologies and prognosis and further these conditions may continue even after the viral load is gone. Accordingly, treatments for these diseases are normally tailored to the particular type of disease no and not just the decrease in the viral load, and there can be no “magic bullet” against all disorders associated with COVID-19 infection. The pathogenesis of these diseases is complex and different. The varied anatomic specificities of each of the disease need to be considered. As disclosed by Wiersinga et al. (JAMA review, 2020. 324(8):789-793), COVID-19 has various clinical manifestations such as fever , dry cough shortness of breath, fatigue, myalgias, nausea/vomiting or diarrhea , headache, weakness and rhinorrhea (mild to severe manifestation and critical manifestation defined by respiratory failure, septic shock, and/or multiple organ dysfunction (Box1 and Box2) (page 786, col.2, 2nd para). They disclose Complications of COVID-19 include impaired function of the heart, brain, lung, liver, kidney, and coagulation system. COVID-19 can lead to myocarditis, cardiomyopathy, ventricular arrhythmias, and hemodynamicinstability (page 786, col.2, para 5). With regards to drugs for treating COVID-19, Wiersinga et al. discloses that following classes of drugs are being evaluated or developed for the management of COVID-19: antivirals (eg, remdesivir, favipiravir), antibodies (eg, convalescent plasma, hyperimmune immunoglobulins), anti-inflammatory agents (dexamethasone, statins), targeted immunomodulatory therapies (eg, tocilizumab, sarilumab, anakinra, ruxolitinib), anticoagulants (eg, heparin), and antifibrotics (eg, tyrosine kinase inhibitors) and that different treatment modalities might have different efficacies at different stages of illness and in different manifestations of disease. (page 788, col.2 last para to page 789, col.1, 1st para). They conclude that Many aspects of transmission, infection, and treatment remain unclear. Advances in prevention and effective management of COVID-19 will require basic and clinical investigation and public health and clinical interventions (page 791, under conclusions).
Further, it is well known and recognized principle in the field of pharmacology especially in enzyme pharmacology, that a compound must have a very characteristic and specific structure to be active as an inhibitor or antagonist, already small changes in the structure of the compound can lead to fundamental changes in the activity. As such treatment of different disorders of COVID-19 is extremely complex and unpredictable.
5-6) The amount of direction or guidance present and The presence or absence of working examples: :
A disclosure should contain representative examples which provide reasonable assurance to one skilled in the art that the compounds which fall within the scope of a claim will have the alleged activity. The only direction or guidance present in the specification the data showing that few of the compounds, specifically about 34 of them shows Mpro inhibition activity in-vitro. Enzyme binding or receptor binding is generally unpredictable and a highly structure specific area, and the data provided is insufficient for one of ordinary skill in the art to extrapolate to the other compounds of the claims and to extrapolate to the actual treatment of COVID-19
The disclosure does not provide how this in vitro data correlates to the treatment of the assorted symptoms associated with COVID-19 claimed. The instant specification is short of any examples or data in regards to the supposed treating of the aforementioned COVID-19 related diseases. Applicants have not provided any competent evidence or disclosed tests that are highly predictive for the pharmaceutical use of the instant compounds. Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved." See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
7-8) The level of skill in the art and the quantity of experimentation:
The level of skill in the art is high. However, due to the unpredictability in the pharmaceutical art, 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 which compounds exhibit the desired pharmacological activity and which diseases would benefit from this activity.
Thus, the specification fails to provide sufficient support of the broad use of the compounds of the instant claims for the treatment and prophylaxis of the various claimed infections/diseases as a result necessitating one of skill to perform an exhaustive search for which disorders can be treated by what compounds of the instant claims in order to practice the claimed invention.
The quantity of experimentation needed is undue experimentation. It would be an undue burden to one skilled in the pharmaceutical arts since there is inadequate guidance given to the skilled artisan, regarding the pharmaceutical use, for the reasons stated above. One of skill in the art would need to determine what diseases are associated with SARS-COV-2 infection or COVID-19, out of the multitude claimed would be benefited (i.e. treated) by the administration of each and every compound encompassed by formula Ib .
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 instant case for the instant method claims. In view of the breadth of the claims, the chemical nature of the invention, the unpredictability of enzyme-inhibitor interactions in general, and the lack of working examples regarding the activity of the claimed compounds towards treating the variety of diseases of the instant claims, one having ordinary skill in the art would have to undergo an undue amount of experimentation to use the instantly claimed invention commensurate in scope with the claims.
Genentech Inc. v. Novo Nordisk A/S (CA FC) 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".. The failure of skilled scientists to achieve a goal is substantial evidence that achieving such a goal is beyond the skill of practitioners in that art,
Also see the PTO website
<<http ://www.uspto.gov/web/offices/pac/dapp/1pecba.htm#7>>
Also, note MPEP 2164.08(b) which states that claims that read on "... significant numbers of inoperative embodiments would render claims nonenabled when the specification does not clearly identify the operative embodiments and undue experimentation is involved in determining those that are operative.". Clearly that is the case here.
Note substantiation of utility and its scope is required when utility is "speculative", "sufficiently unusual" or not provided. See Ex parte Jovanovics, 211 USPQ 907, 909; In re Langer 183 USPQ 288. Also note Hoffman v. Klaus 9 USPQ 2d 1657 and Ex parte Powers 220 USPQ 925 regarding type of testing needed to support in vivo uses.
MPEP 2164.01 (a) states, "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)." That conclusion is clearly justified here. Thus, undue experimentation will be required to make Applicants' invention.
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-11 and 13-14 are rejected under 35 U.S.C. 103(a) as being unpatentable over by Saksena et al. (WO 03/062265, referenced in IDS dated 10/02/2023)
Instant claims are drawn to a compound of Formula (1b):
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or a salt thereof, wherein: R1 and Ria are independently H, a C1-6 saturated hydrocarbon group optionally substituted with 1 to 6 fluorine or chlorine atoms or a benzyl group optionally substituted with 1 to 6 fluorine or chlorine atoms or R1 and Ria are linked together to form a saturated ring optionally containing an additional heteroatom; R2 is a C3-5 saturated hydrocarbon group containing a cycloalkyl group optionally substituted with one or more substituents chosen from fluorine or hydroxyl; R3 is a saturated group containing 3-5 carbon atoms and optionally containing a cycloalkyl group or optionally containing a saturated ring containing an oxygen heteroatom and optionally substituted with one or more substituents chosen from fluorine, or hydroxyl or R3 is CH2aryl, CH(CH3)aryl or C(CH3)2aryl; and R5 is a C2-8 hydrocarbon group, optionally containing one or more rings or a double bond and which is optionally substituted with one or more groups selected from fluorine; chlorine; bromine; cyano; hydroxy; methoxy; amino; or a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group.
Sexana et al. discloses the following compounds (2nd , 4th and 5th compounds on page 416
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These compounds differ from the current compounds on account of different groups than current group R5. However , they disclose the following compound (page 567, 4th compound) has nine carbon atoms instead of 2-8 as required for current group R⁵
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In contrast thereto, the third compound on page 426
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only differs from the current compounds on account of lacking the cycloalkyl group required by current group R₂, whereas the following sixth compound on page 443 contains
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current groups R⁵ and R², however, not current group R¹.
In other words, Saxena et al. discloses the qualitative interchangeability of various functional groups, and i.e. specifically discloses current groups R⁵ and R², also in combination. As such it would have been prima facia obvious to a person of ordinary skill in the art to arrive at the instant claims motivated and guided by the generic compounds and specific compounds taught by Saxena et al.
Wiith regards to the functional limitation set forth in claim 13 which is the compounds having SARS CoV-2 Mpro inhibitor activity, Saxena et al. does not teach this activity. However they disclose structurally similar compounds useful as antiviral agents and absence of evidence to the contrary, this functional limitation of the compound will be achieved by following the active method steps taught by Saxena et al. It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph). It is noted that, if the prior art discloses identical chemical structure, the properties applicant discloses and/or claims are necessarily present, In re Spada, 911 F.2d 705, 709, 15 USPQ2d. As such a person of ordinary skill in the art would be imbued with a reasonable expectation of success in treating all types of breast cancer with the instantly claimed compound, absence of evidence to the contrary.
Conclusion
Claims 1-11, 13-14 and 16-19 are rejected. Claim 12 is allowable
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAVITHA RAO whose telephone number is (571)270-5315. The examiner can normally be reached on Mon-Fri 7 am to 4 pm..
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Dierdre (Renee) Claytor can be reached on (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAVITHA M RAO/Primary Examiner, Art Unit 1691