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 .
Election/Restrictions
Applicant’s election without traverse of SARS-CoV (virus) and a condition associated with kidney transplant.
Claims 1, 4, 6-10, 13-14, 16-19, 21-22, 24-25, 28 and 35-36 are pending.
Claims 1, 4, 6-10, 13-14, 16-19, 21-22, 24-25, 28 and 35-36 read on the elected species and are under consideration.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4, 6-10, 13-14, 16-19, 21-22, 24-25, 28 and 35-36 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 treatment of SARS-CoV-2, does not reasonably provide enablement for treatment or preventing of all viruses (including SARS-CoV-2) with voclosporin. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
As stated in 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.”
The factors to be considered when determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, were described in In re Wands, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) as:
1. the nature of the invention;
2. the breadth of the claims;
3. the state of the prior art;
4. the relative skill of those in the art;
5. the predictability or unpredictability of the art;
6. the amount of direction or guidance presented [by the inventor];
7. the presence or absence of working examples; and
8. the quantity of experimentation necessary [to make and/or use the invention.
(1) The Nature of the Invention (2) The Breadth of the claims
Claim is directed a method of treating or preventing a virus infection in a subject comprising administering to the subject a therapeutically effective amount of voclosporin.
The claims will be given its broadest reasonable interpretation. The applicable rule for interpreting the claims is that “each claim must be separately analyzed and given its broadest reasonable interpretation in light of and consistent with the written description.” See MPEP 2163(II)(1), citing In re Morris, 127 F.3d 1048, 1053-1054; 44 USPQ2d 1023, 1027 (Fed. Cir. 1997). In view of this rule, Claim 1 is drawn to treatment or preventing of any virus with voclosporin.
(3) The state of the prior art and (5) The predictability or unpredictability of the art
The instant application is enabling for treatment of SARS-CoV-2 with voclosporin. However, the art is silent regarding preventing and treating all viruses with voclosporin.
The state of the art is that there are some antiviral medication that exist for specific viruses. For example, acyclovir for the treatment of HSV is shown to shorten the duration of symptoms, but there is no drug to completely prevent HSV (<Treating herpes - Herpes Viruses Association> accessed 4/30/26). However, the state of the art is that many viruses cannot be treated and/or prevented, with treatment focusing on relieving symptoms. For example, specific treatment options for Hantavirus is limited (<Hantavirus pulmonary syndrome - Diagnosis & treatment - Mayo Clinic> accessed 4/30/26).
Therefore, the state of the art at the time of the application is that the etiology and treatment of the viruses is not well understood and therapy is challenging and complex. Adding to the complexity are the many different viruses. Therefore, it would be highly unlikely and require undue experimentation to determine is voclosporin could treat and prevent all viruses.
It is noted that pharmaceutical and biological art is generally unpredictable, requiring each embodiment to be individually assessed for physiological activity. Furthermore, viruses are highly diverse with distinct structures, replication, host interaction and therapeutic susceptibilities. Importantly, it is known in the art that there is not a clear understanding of the origins and pathophysiology of many emerging viruses. Given this fact, historically the development of antivirals has been difficult and time-consuming. Adding to the unpredictability is that many treatment options may show promise in animal models, but may fail to show therapeutic improvement in clinical trials. There is no absolute predictability, even in view of the high level of skill in the art.
(4) The relative skill of those in the art
MPEP 2141.03 states (in part)” A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR International Co. v. Teleflex Inc., 127 S.Ct. 1727, 167 LEd2d 705, 82 USPQ2d 1385, 1397 (2007). “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. At 1396, 82 USPQ2d at 1396. The “hypothetical person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988) (disagreeing with the examiner’s definition of one of ordinary skill in the art (i.e. a doctorate level engineer or scientist working at least 40 hours per week in semiconductor research or development), and finding that the hypothetical person is not definable by way of credentials, and that the evidence in the application did not support the conclusion that such a person would require a doctorate or equivalent knowledge in science or engineering). In the instant case, the skill in the art high with respect to physicians and scientists. The level of skill in the art (physicians and scientists) would be high.
(6) The amount of direction or guidance presented (by the inventor) and (7) The presence or absence of working examples
The applicant provided sufficient guidance or direction regarding the potential treatment of SARS-CoV-2 with voclosporin. Applicants provide in vitro data showing the inhibition of COVID-19 in cell culture and inhibition of viral replication. The specification discloses in vivo studies, however the results of the studies are not presented (see [0123-0124]. However, the in vitro supports treatment of SARS-CoV-2 with voclopsorin.
In contrast, the applicant provides little in way of direction or guidance regarding treating or preventing other viruses. There was no disclosure of treating other viruses or preventing any virus.
Therefore, the specification and working examples provided by the applicant support treatment of SARS-CoV-2 with voclosporin.
(8) The quantity of experimentation necessary (to make and/or use the invention)
Owing to the factors listed above, especially in points 6 and 7, the amount of experimentation needed will be extensive in view of the lack of guidance by the inventor. 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.
The instant breadth of the claim is broader than the disclosure, specifically, the instant claims are directed to the treatment and preventing of all viruses with voclosporin, but the specification, prior art or instant disclosure does not provide support for this.
In conclusion, the instant application is enabled for the treatment of SARS-CoV-2 with voclosporin.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 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.
Claims 1, 4, 6-8, 13, 19, 21-22, 24-25, 28 and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Rodriguez-Cubillo et al. (Am J Transplant 2020:20;3173-3781) in view of Li et al. (Clinical Pharmacology: Advances and Applications 2020;12 83-96).
Rodriguez-Cubillo et al. teach minimizing immunosuppression and administration of antiretrovirals have been recommended for kidney transplant recipients with COVID-19, but outcomes remain poor. Rodrigues-Cubillo et al. teach that cyclosporin (CsA) has a likely benefit due its antiviral and immunomodulatory effect (Abstract). Rodrigues-Cubillo et al. teach a study comprising 29 kidney transplant recipients (KTRs) with COVID-19 (Abstract). Rodriguez-Cubillo et al. teach CsA could have an antiviral effect in patients with coronavirus (p. 3177, bottom of 2nd col.). Rodriguez-Cubillo et al. teach “CsA is a well-known immunosuppressive drug that binds to cellular cyclophilins to inhibit calcineurin. The inhibition of calcineurin blocks the transcription of genes encoding cytokines such as interleukin-2. This effect is useful as immunomodulator and immunosuppressant agent in kidney transplant recipients. Interestingly, many viruses require cyclophilins for replication, including the coronavirus, so cyclosporine could suppress its replication.” (p. 3177, bottom of 2nd col.). Rodriguez-Cubillo et al. teach that
Rodriguez-Cubillo et al. further states that given that SARS-CoV-2 is associated with cytokine release syndrome, CsA might be helpful with the hyperinflammatory phase of SARS-CoV-2 infection (p. 3178, 1st para.). Rodriguez-Cubillo et al. teach Group I: mycophenolate and/or rapamycin were discontinued and the dose of calcineurin inhibitors was reduced; Group 2: cyclosporin based immunosuppressive therapy (CsA). Table 4 discloses that mortality was higher in Group I (50%) vs. Group 2 (13%). Rodriguez-Cubillo et al. states that renal function did not deteriorate and CsA treated could be safe and effective for KTRs diagnosed with COVID-19 (Abstract).
Rodriguez-Cubillo et al. does not teach administration of voclosporin. However, the teachings of Li et al. cure this deficiency.
Li et al. teach voclosporin is a more potent derivative of cyclosporine (Abstract). Li et al. teach that voclosporin is better tolerated and safer that cyclosporine (Abstract). Li et al. teach that the drugs have similar structure and mechanism of action, however the high potency and low dose compounded by the non-linear disposition of voclosporin resulted in more systemic vs local calcineurin inhibition than with cyclosporin (Abstract).
With respect to claim 1, it would have been obvious to a person of ordinary skill in the art to use voclopsorin in place of CsA for the treatment of COVID-19 in kidney transplant recipients because Li et al. teach it is a more potent derivative of CsA that is better tolerated and safer. There is a reasonable expectation of success given that CsA and voclosporin are known calcineurin inhibitors and similar biological effects would be expected due to the similar structure and mechanism of actions.
With respect to claims 4 and 6-8, Rodrigues-Cubillo et al. teach a study comprising 29 kidney transplant recipients (KTRs) with COVID-19 (Abstract). COVID-19 is caused by SARS-CoV-2.
With respect to claim 13, teach renal function was monitored (p. 3176, 2nd col., 5th para, Table 3, Abstract).
With respect to claims 19 and 21-22, Rodrigues-Cubillo et al. teach a study comprising 29 kidney transplant recipients (KTRs) with COVID-19 (Abstract). COVID-19 is caused by SARS-CoV-2.
With respect to claim 24, Rodriguez-Cubillo et al. teach mycophenolate was discontinued (p. 3174, para. 2.3.1; p. 3177 top of 1st col.).
With respect to claim 25, Rodriguez-Cubillo et al. teach that most patients were treated with mycophenolate and low dose of steroids and that mycophenolate was discontinued (p. 3177 top of 1st col.). Rodriguez-Cubillo et al. teach that early administration of high dose of steroids in 18 patients (p. 3177, 1st col. 5th para. and Table 4).
With respect to claim 28, Li et al. teach oral administration of voclosporin (p. 89, bottom of 1st col.; Table 2, Table 3).
With respect to claims 35 and 36, Rodriguez-Cubillo et al. and Li et al. make obvious administration of voclosporin for treatment of COVID-19 in kidney transplant patients. With respect to the limitation “viral load is reduced in the subject following administration of voclosporin” and “wherein the survival of the subject is extended following administration of voclosporin”, administration of voclosporin to KTRs with COVID-19 made obvious by Rodriguez-Cubillo et al. and Li et al. would inherently have all of the activities and properties of the composition of claim 1. The MPEP § 2112 states: “Once a reference teaching product appearing to be substantially identical is made the basis of a rejection, and the Examiner presents evidence or reasoning tending to show inherency, the burden shifts to the Applicant to show an unobvious difference ‘[t]he PTO can require an Applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on inherency’ under 35 U.S.C. 102, on prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same…[footnote omitted].” The burden of proof is similar to that required with respect to product-by-process claims. In re Fitzqerald, 619 F.2d 67, 70, 205 USPQ 594, 596 (CCPA 1980) (quoting In re Best, 562 F.2d 1252, 1255, 195 USPQ 430,433- 34 (CCPA 1977)).” In other words, Rodriguez-Cubillo et al. and Li et al. make obvious administering the same composition to the claimed patient population, therefore the viral load and survival extension would necessarily occur. Furthermore, Rodriguez-Cubillo et al. a reduction in mortality in the group treated with CsA. Moreover, MPEP 2112.01 states: “Products of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Importantly, MPEP 2112 states: “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer” and “There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference.
Claims 9-10, 14 and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Rodriguez-Cubillo et al. and Li et al. as applied to claims 1, 4, 6-8, 13,19, 21-22, 24-25, 28 and 35-36 above, and further in view of Lupkynis (FDA highlights of prescribing information, published 1/2021).
Please note that Lupkynis is voclosporin.
Rodriguez-Cubillo et al. and Li et al. do not teach the therapeutically effective dose of voclosporin or monitoring renal function of claim 14. However, the teachings of Lupkynis cures this deficiency.
Lupkynis teaches the recommended starting dose is 23.7 mg orally twice a day (p. 1, 1st col.), meeting the limitation of claim 10. It would have been obvious to a person of ordinary skill in the art to use the recommended dose of voclosporin as indicated by the FDA for safety. There is a reasonable expectation of success given that Lupkynis teaches the recommended dose and disclosed modifications based on renal function.
With respect to claim 9, if the average human weight 70 kg, 23.7 mg twice a day is a total of 47.4 mg/day. 47.4 mg/70kg is equal to 0.677 mg/kg/day and is within the claim dose of claim 9.
With respect to claims 14 and 16-18, Lupkynis teaches the dose is modified based on the eGFR and meets the limitations of claims 14 and 16-18. Lupkynis states (p. 1, 1st col.):
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Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TARA L MARTINEZ whose telephone number is (571)270-1470. The examiner can normally be reached Mon-Fri 8:00-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached at (571)270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TARA L MARTINEZ/ Examiner, Art Unit 1654
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