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
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as the elected species.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-16 and 18-21 are examined together.
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 1-16 and 18-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), 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.
To be enabling, the specification of the patent application 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 (Fd. 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). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). These include: (1) breadth of the claims; (2) nature of the invention; (3) state of the prior art; (4) amount of direction provided by the inventor; (5) the level of predictability in the art; (6) the existence of working examples; (7) quantity of experimentation needed to make or use the invention based on the content of the disclosure; and (8) relative skill in the art.
All of the factors have been considered with regard to the claims, with the most relevant factors discussed below: 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:
Claims 1-16 and 18-21 recite a method of treating coronavirus infection, comprising administering an TLR 7/8 inhibitor, such as compounds of claim 5, to a subject 5.
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicant’s invention would generally be a physician with a M.D. degree and several years of experience.
State of the art with respect to TLR 7 antagonists (such as hydroxychloroquine or chloroquine) for treatment of coronavirus (more on TLR7/8 biology, working example, direction and guidance later): As illustrative of the state of the art regarding the treatment of COVID-19 with TLR-7 antagonists, reference is made to the following: NIH COVID-19 Treatment Guidelines (August 27, 2020) at: https://web.archive.org/web/20200828170647/https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/chloroquine-or-hydroxychloroquine-with-or-without-azithromycin/
and
post filing Schilling, Expert Opinion on Pharmacotherapy (2021) 22:1257-1266.
The NIH reference teaches that, even though hydroxychloroquine demonstrated antiviral activity in vitro, it did not reduce upper or lower respiratory trac viral loads or demonstrate clinical efficacy in rhesus macaque model. Also, in a large randomized controlled trial of hospitalized patients in the UK, hydroxychloroquine did not decrease 28-day mortality when compared to the usual standard of care. Participants who were randomized to receive hydroxychloroquine had a longer median hospital stay than those who received the standard care. In addition, among patients who were not on invasive mechanical ventilation at the time of randomization, those who received hydroxychloroquine were more likely to subsequently require intubation or die during hospitalization than those who received standard care. The reference concludes: ”given the lack of benefit seen in the randomized clinical trials and the potential toxicity, the Panel recommends against using hydroxychloroquine or chloroquine to treat COVID-19 in hospitalized patients”. Schilling, like the NIH reference teaches: “In hospitalized patients with severe COVID-19, Randomized Clinical Trials show clearly that 4-aminoquinolines are NOT beneficial” (see abstract). In summary, the NIH and Schilling references teach, that contrary to Applicant’s claim , that is treating a coronavirus infection in a subject in need thereof, comprising administering an effective amount of a TLR 7/8 inhibitor) , that the TLR-7 antagonists: chloroquine and hydroxychloroquine not only do not show efficacy in treating COVID-19, but the opposite is true: it was detrimental when compared with standard care.
In addition, it is noted that disinfectants have been suggested for the treatment of COVID-19, see https://www.bbc.com/news/world-us-canada-52399464,
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The above teaching by President Donald Trump, presumably based on Trump’s prior knowledge of TLR pharmacology, for example relating to the disclosure in Ofodile, J Ind Microbiol Biotechnol (2007) 34:751–762. As per Ofodile “disinfectants, like the common antiseptic Disifin (sodium tosylchloramide), interact with the body's innate immune system, particularly Toll-like Receptors (TLRs), which recognize pathogens; while disinfectants directly kill microbes, they also trigger TLRs (like TLR4, TLR2) to initiate inflammatory responses and antimicrobial actions (like producing reactive oxygen species, ROS) via pathways involving MyD88, potentially overlapping in function but differing in mechanism, with research focusing on using TLR modulators (agonists/antagonists) for better immune control against infections”. Thus TLR7 and TLR8 are inexorably linked to Disifin’s biological property See Ofodile, page 754 column A section under Toll-like receptors. Even though Trump’s advice could have saved millions of people from coronavirus death, medical experts disputed the idea of using disinfectants. see https://www.bbc.com/news/world-us-canada-52407177, because the predictable use of Disifin or any other TLR7/8 modulating disinfectants for the treatment of corona virus is not supported by the state of the art.
As to working example, direction and guidance relevant instant disclosure include the following:
In vitro data relating to chloroquine and hydroxychloroquine compared to the compound 3, M5049 (the elected species and compound of claim 6) are found in the Figures 2A-3D and Figures 7A-9A.. The observed data show that M5049 is more potent than chloroquine and hydroxychloroquine. However, this is not supportive of enabling disclosure needed given the unpredictability in the art and cautionary teachings of NIH and Schilling regarding these TLR antagonists (see rejection under 103), because one of skill in the art would understand that higher doses of CQ and HQ in the context of lower IC50/EC50 could possibly overcome potency related issues. Working Examples relevant with respect to In Vivo Effect of Administration of M5049 is found in Example-10, [0141] of the specification and at Figures 9A and 9B. M5049 reduced both gene signature scores at 1 and 10 mg/kg indicating that M5049 distributes well to the lung and potently reduces lung inflammation. This is consistent with the teachings in a Review on Micro-RNAs in the regulation of immune response against SARS CoV-2 and other viral infections, Tareq Abu-Izneid, Journal of Advanced Research 30 (2021) 133–145. According to Tareq, miR-122 is one of the reported miRNAs that showed a positive effect on viral replication (increased viral replication). Host miR-122 works by direct miRNA-virus interaction with the hepatotropic virus (HCV is a positive-sense ssRNA genome), leading to increased viral RNA accumulation/increase virus replication. Micro-RNAs (miRNAs) regulate the immune response to viral infections, including SARS-CoV-2, by controlling gene expression at the post-transcriptional level. They can either suppress or enhance immune responses by targeting viral or host RNAs, affecting key pathways like the interferon (IFN) signaling cascade. This makes them potential therapeutic targets for new antiviral treatments. Tareq teaches under section ‘Future perspectives and conclusion, “miR-122 has a high level of specific expression in the hepatocyte, therefore, blocking miR-122 will only show action in the liver. Biologists believe that a certain number of miRNAs are upregulated in association with certain diseases or infections. Notably, the expression of these specific miRNAs in certain infectious states makes it critical to identify disease biomarkers and develop novel techniques to target viral infections like COVID-19 for diagnosis and treatment. Under section Promises of miRNAs as the future of medical intervention, Tareq teaches ‘For a miRNA to be considered as an optimal drug target, it needs to have an expression that is specific for certain tissue. A good example will be the miR-122 that have specific expression inside hepatocyte therefore, miR-122 inhibitor will only show effects in hepatocyte’ As such, potently reducing lung inflammation by administration previously known M5049 is not the same as using any and all TLR 7/8 inhibitors to treat coronavirus infection or any and all laundry list of clinical indications as listed in claim 10. Further, in applications attention is directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). This is because it is not obvious from the disclosure of one species, what other species will work”.
According to MPEP 2164 The Enablement Requirement [R-11.2013] , for a claimed genus, representative examples together with a statement applicable to the genus as a whole will ordinarily be sufficient if one skilled in the art (in view of level of skill, state of the art and the information in the specification) would expect the claimed genus could be used in that manner without undue experimentation. Proof of enablement will be required for other members of the claimed genus only where adequate reasons are advanced by the examiner to establish that a person skilled in the art could not use the genus as a whole without undue experimentation.
Where the assertion of utility is unusual, difficult to treat or speculative, the examiner has authority to require evidence that tests relied on are reasonably predictive of in vivo efficacy by those skilled in the art. See for example, In re Ruskin 148 USPQ 221; Ex parte Jovanovics 211 USPQ 907. Note MPEP. 2164.05(a).
MPEP2164.01(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.
Genentech Inc. v. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001, 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”.
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.
Claim(s) 1-4, 7-14, 21 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Vabret, Immunity 52, June 16, 2020 Available on line 6 May 2020.
Note instant priority 14 May 2020
Vabret teaches therapeutic strategies to prevent or treat SARS-CoV-2 infection. In particular, Vabret teaches the utility of the TLR7 inhibitors chloroquine and hydroxychloroquine in the treatment of SARS-CoV-2 infection at page 924, column A.. Thus, Vabret at least anticipates the subject-matter of present claims 1-4, 7-14, 21.
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 1-16 and 18-21 are rejected under 35 U.S.C. 103 as being unpatentable over Frieman, US 20170027975. Sherer, WO 2020025517 (= US provisional 62712439 date 31 July 2018) and Wang Cell Research (2020) 30:269–271 Published 4 February 2020 and Garulli, Clinical and Vaccine immunology, Oct 2008, 1497-1504.
Frieman teaches method for treating a coronavirus infection in a subject, comprising the steps of: administering to said subject a therapeutically effective amount chloroquine, hydroxycloroquine (see Frieman claims 17 and 20). According to Wang, chloroquine effectively inhibit the coronavirus (2019-nCoV). Further, at page 269 column B, starting at the last paragraph, Wang teaches pharmacological utility of Chloroquine reading on the limitations of dependent claims with respect to clinical indications such as in claim 10. Neither Frieman or Wang teach that Chloroquine as TLR7/8 inhibitor. However, this inherent property of Chloroquine, hydroxychloroquine are as established inhibitors of TLR 7/8. Also see NIH and Schilling referenced elsewhere in this action).
Sherer teaches at page 185, Example 151, the compound of instant claim 6 (and generically the elected species, the first compound of claim 5) and pharmaceutically acceptable compositions thereof, useful as TLR7/8 antagonists.
Taken together, because of the inherent TLR7/8 antagonist property of the instantly exemplified claimed compounds being same as the inherent property of Chloroquine, the limitations of instant claims with respect to the critical factors of active ingredients and the disease state being treated are obvious to one of skill in the art. Limitations of dependent claims such choosing the patients 11-16 or optimizing duration of treatment and doses claims 11-16, 18-21) are within the repertoire of one of skill in the art. There is nothing in the specification with respect to these limitations for secondary considerations. Obviousness can be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art.
As such there is nothing unobvious in these claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIZAL S CHANDRAKUMAR whose telephone number is (571)272-6202. The examiner can normally be reached M-F 8-5 EST.
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/NIZAL S CHANDRAKUMAR/ Primary Examiner, Art Unit 1625