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 .
Current Status of 18/022,963
The Office Action is responsive to the claims of 23 February 2023. Claims 1-2,4,6-7,9-13,15,17,21-25 and 27-28 have been examined on the merits.
Priority
The instant application is a nation stage entry of PCT/US2021/047128, international filing date 23 August 2021, which claims prior to U.S. Provisional No. 63/069,313, filed 24 August 2020.
The claims find support in 63/069,313 and are given the effective filing date of 24 August 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 23 February 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because Figure 5 is grainy and difficult to read. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities: The prodrug structure on pg. 14 of the specification is grainy and illegible
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Replacement of the figure with a clear, legible structure will render this objection moot.
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, 2, 4, 6, 7, 9-13, 15, 27, and 28 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 written description requirement. The claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Factors to be considered in making the determination as to whether one skilled in the art would recognize that the application was in possession of the claimed invention as a whole at the time of filing include: (a) Actual reduction to practice; (b) Disclosure of drawings or structural chemical formulas; (c) Sufficient relevant identifying characteristics such as : (i) Complete structure, (ii) Partial structure, (iii) Physical and/or chemical properties or (iv) Functional characteristics when coupled with a known or disclosed correlation between function and structure; (d) Method of making the claimed invention; (e) Level of skill and knowledge in the art and (f) Predictability in the art. While all of these factors are considered, a sufficient number for a prima facie case are discussed below.
The specification fails to provide adequate support for the full scope of thiazolide agents of base claims 1, 10 and 12, drawn to a method of treating illness caused by a virus of the Coronaviridae family, a method of preventing viral respiratory illness, and a method of treating a mild or moderate illness caused by severe acute respiratory syndrome coronavirus 2, respectively. The thiazolide agents are defined by their ability to produce an effective concentration of tizoxanide in a plasma in a plasma of the subject.
The specification provides examples of nitazoxanide and active metabolites of nitazoxanide (pg. 3-4), literature for the synthesis of thiazolide compounds and compositions containing nitazoxanide and applications thereof (pg. 4-5), prodrugs of tizoxanide, including nitazoxanide (pg. 14-15), and compositions containing thiazolide agents, such as tizoxanide and pharmaceutically acceptable salts and prodrugs thereof (pg. 15-19). The specification also provides examples of clinical trials using nitazoxanide to assess the efficacy of the compound to treat viral respiratory illnesses, including SARS-CoV-2 (pg. 30-75).
While the specification provides examples of thiazolide agents that may be capable of producing an effective concentration of tizoxanide in a plasma of a subject, it does not demonstrate possession of all compounds that could produce an effective concentration of tizoxanide in the plasma of a subject.
The broadest reasonable interpretation permits the thiazolide agent to be any agent that produces the effects described above. When base claims 1, 10 and 12 are analyzed using the broadest reasonable interpretation, Applicants have possession of the methods using nitazoxanide as the thiazolide agent for the methods of treatment.
Therefore claims 1, 10 and 12 are rejected as lacking written description support. Furthermore claims 2, 4, 6, 7, 9, 11, 13, 15, 27, and 28 are similarly rejected since these claims do not remedy the rejections against the base claims from which they depend.
Claims 10 and 11 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 claims 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 factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to a method of preventing a viral respiratory illness in an asymptomatic subject through the administration of an effective amount of a thiazole agent. Instant claim 11 further specifies that the viral respiratory illness is of the Coronaviridae family. Thus, the claims taken together with the specification imply that the claimed method of administration of a thiazolide agent is capable of preventing all viral respiratory illnesses broadly (claim 10) and capable of preventing all viral respiratory illnesses cause by the Coronaviridae family. Additionally, the thiazole agents encompass an undefined number that are defined only by their desired functional activity. Thus, the claims are extremely broad and encompass all thiazolide agents, including those not found in the disclosure.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The prior art does not teach that tizoxanide is capable of prophylactic treatment of human subjects with viral respiratory infections. At the time of filing, the art disclosed that nitazoxanide, when administered with oseltamivir, showed prophylactic activity against influenza infection in a preclinical ferret model (Mifsud). However, this evidence is limited to influenza and does not establish or suggest prophylactic efficacy in coronaviruses or in humans.
The current state of the art is that nitazoxanide has no significant effect on infection with SARS-CoV-2 among healthcare workers or others at high risk of infection (Sokhela).
Chemistry is an unpredictable art, see MPEP 2164.03.
(5) The relative skill of those in the art:
The artisan is someone with knowledge in virology, pharmacology, medicinal chemistry, or a related biomedical discipline, with experience in antiviral drug development or clinical treatment of viral infections.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification has provided several working examples and clinical data demonstrating the therapeutic efficacy of nitazoxanide in symptomatic COVID-19 patients. The presented data shows outcomes like reduced viral load, decreased progression to severe disease, and improved clinical recovery (Examples 1-5, pgs. 30- 75).
However, the specification does not provide any examples or data demonstrating that the method is capable of preventing infection or illness in asymptomatic subjects, presymptomatic subjects, or healthy individuals. There is no information in animal or human models that shows prevention of infection or disease onset.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the references above, particularly with regards to the lack of evidence supporting prophylaxis of viral infections through administering thiazolide agents and the high unpredictability in the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in the scope of the claims.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
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 1, 2, 4, 6, 7, 9-13, 15, 17, 21-23, 27, and 28 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.
Base claims 1, 10, and 12 recite “an effective amount of a thiazolide agent to produce an effective concentration of tizoxanide in a plasma of the subject.” This phrase is indefinite because it defines the amount of thiazolide agent only in terms of achieving an “effective concentration” of tizoxanide. The specification fails to provide objective boundaries for what constitutes such an “effective concentration.” Therefore, the claims do not describe the metes and bounds of the claimed invention with reasonable certainty. Claims 2, 4, 6, 7, 11, 13, 15, 17, 21-23, 27, and 28 do not remedy this issue and are similarly rejected.
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.
Claims 1, 2, 4, and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Reyoung (CN 111544431, found in IDS submitted 02/23/2023) as evidenced by Gilles (Gilles, Herbert M., and Paul S. Hoffman. "Treatment of intestinal parasitic infections: a review of nitazoxanide." Trends in parasitology 18.3 (2002): 95-97).
Reyoung teaches that tizoxanide is the active metabolite of nitazoxanide in vivo (pg. 2). Although Reyoung does not explicitly disclose the location of tizoxanide, the production of tizoxanide in the plasma is an inherent property of the metabolism of nitazoxanide. Evidentiary reference Gilles demonstrates that upon administration of nitazoxanide to a subject, metabolite tizoxanide is present in human plasma (Fig. 1). Accordingly, the limitation that tizoxanide is in the plasma of the subject is an inherent characteristic of the disclosure of Reyoung.
The reference teaches the application of nitazoxanide in preparation of drugs for prevention and treatment of interstitial lung disease (ILD) (pg. 1) and teaches the use of the nitazoxanide for the prevention and treatment of ILD where the active ingredient if tizoxanide (Claim 2). The ILD includes disease complications caused by coronavirus infection including severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and new coronavirus pneumonia. The coronaviruses include SARS virus (SARS-CoV), MERS coronavirus (MERS-CoV) and new coronavirus (SARS-CoV-2) (pg. 2). Although Reyoung does not expressly state that the subjects display symptoms of an illness caused by the Coronaviridae family, such as SARS-CoV2, these symptoms are inherent to illnesses caused by this family of viruses. By definition, an “illness” is defined as a condition characterized by the presence of symptoms that affect an individual’s health, often requiring diagnosis and treatment (see https://www.sciencedirect.com/topics/medicine-and-dentistry/illness). This means that a subject with an illness caused by the Coronaviridae family is unwell and necessarily exhibits one or more clinical symptoms. In contrast, asymptomatic subjects of Coronaviridae viruses do not constitute illness, as the subjects remain well and do not display symptoms. The symptoms associated with a Coronaviridae caused illness are similarly inherent. If a subject is suffering from a Coronaviridae caused illness, then they have symptoms associated with Coronaviridae. These symptoms are known and include fever, chills, cough, shortness of breath, difficulty breathing, sore throat, congestion, runny nose, new loss of taste or smell, fatigue, body aches, headache, nausea, vomiting, and diarrhea (see https://www.cdc.gov/covid/signs-symptoms/index.html). Thus, the recitation that the subject displays one or more symptoms of the illness does not rendering the instant claims novel over Reyoung because the presence of symptoms is an inherent feature of the illness itself.
Although Reyoung does not explicitly disclose that a subject suffering from a Coronaviridae caused illness exhibits an oral temperature of no less than 37.3°C, these feature is inherent to fever. Fever is a recognized hallmark symptom of Coronaviridae caused illness, and clinical references define fever as an elevated oral temperature greater than 37.5°C (see Penn Med). Thus, the recited temperature threshold of instant claim 4 falls within this range, and the limitation is an inherent property of a subject suffering from Coronaviridae caused illness.
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 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, 6, 7, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Reyoung in view of Fehr (Fehr, A.R., Perlman, S. (2015). Coronaviruses: An Overview of Their Replication and Pathogenesis. In: Maier, H., Bickerton, E., Britton, P. (eds) Coronaviruses. Methods in Molecular Biology, vol 1282. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2438-7_1).
Determining the scope of the prior art:
The teachings of Reyoung are discussed above and incorporated by reference into this rejection. The reference teaches the limitations of claim 1.
Fehr teaches that coronaviruses can cause a variety of disease in mammals including respiratory infections in humans (pg. 1, Abstract). The reference also teaches that coronaviruses are the largest group of viruses belonging to the Nidovirales order which includes Coronaviridae (pg. 1, first para), reading on instant claim 6. Coronavirinae is one of the subfamilies of Coronaviridae and is further subdivided into four genera, the alpha, beta, gamma, and delta coronaviruses (pg. 1, first para), reading on instant claim 7. 229E and NL63 are known alphacoronaviruses, and HKU1 and OC43 are known betacoronaviruses (pg. 12, section 5.2), reading on instant claim 9.
Ascertaining the differences between the prior art and the claims at issue:
Reyoung does not explicitly teach that a virus of the Coronaviridae family is the sole cause of the illness.
Fehr does not teach a method of treating coronaviruses using a thiazolide agent.
Resolving the level of ordinary skill in the pertinent art:
Those of relevant skill in the art are those with the level of skill of the inventors of the references cited to support the Examiner’s positions.
Considering objective evidence present in the application indicating obviousness or nonobviousness:
The artisan, having recognized that coronaviruses are classified within the Coronaviridae family and further subdivided into alpha and beta genera that include human coronaviruses such as NL63, KHU1, 229E, and OC43, would have been motivated to apply the method taught by Reyoung to illnesses caused by these specific viruses. Reyoung broadly teaches the use of a thiazole agent to treat and prevent coronavirus associated ILD. In view of the common taxonomic and clinical knowledge that alpha and beta coronaviruses responsible for such illness, it would have been obvious to limit Reyoung’s teachings to be specific to these particular genera and species. The artisan would expect the treatment to be effective against these coronaviruses for the same reasons Reyoung teaches efficacy against coronavirus induced disease generally.
Claims 12, 13, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Reyoung in view of Ng (Effects of oseltamivir treatment on duration of clinical illness and viral shedding and household transmission of influenza virus. Clin Infect Dis. 2010 Mar 1;50(5):707-14. doi: 10.1086/650458. PMID: 20121573; PMCID: PMC2840043.) and Roos (https://www.cidrap.umn.edu/h1n1-2009-pandemic-influenza/studies-oseltamivir-use-drops-evidence-benefits-grows).
Determining the scope of the prior art:
The teachings of Reyoung are discussed above and incorporated by reference into this rejection. The reference teaches the limitations of claim 12.
Ng teaches that early oseltamivir treatment reduced time to alleviation of influenza symptoms by 1 to 2 days (pg. 5, para. 4). Oseltamivir is a neuraminidase inhibitor used for the treatment of influenza virus infection (Introduction, pg. 2).
Roos teaches that the standard recommendation for using oseltamivir and similar drugs in influenza patients is that treatment should begin within 48 hours after the first symptoms and that a trial shows that treatment up to 72 hours after symptom onset is still beneficial (first para.).
Ascertaining the differences between the prior art and the claims at issue:
Reyoung does not explicitly teach that the treatment method reduces the symptom duration of subjects and does not specify that administration of the agent is performed within 72 hours of the onset of mild or moderate illness in the subject.
Ng and Roos do not teach a method of treating coronavirus caused illness using a thiazolide agent.
Resolving the level of ordinary skill in the pertinent art:
Those of relevant skill in the art are those with the level of skill of the inventors of the references cited to support the Examiner’s positions.
Considering objective evidence present in the application indicating obviousness or nonobviousness:
The artisan would have been aware that administration of antiviral drugs within 72 hours of symptom onset provides superior clinical outcomes, including reduction in symptom duration and illness severity. The artisan would have been motivated to administer the thiazolide agent of Reyoung within this same 72 hour window following the onset of mild or moderate coronavirus symptoms and would expect that such early treatment would similarly shorten symptom duration and improve clinical outcomes.
Claims 1, 17, and 21-28 are rejected under 35 U.S.C. 103 as being unpatentable over Reyoung in view of Haffizulla (Haffizulla, Jason, et al. "Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial." The Lancet Infectious diseases 14.7 (2014): 609-618), and Pharmaceutics (Pharmaceutics: Drug Delivery and Targeting).
Determining the scope of the prior art:
The teachings of Reyoung are discussed above and incorporated by reference into this rejection. The reference teaches the limitations of claim 1. Reyoung also lists specific dosage forms of the pharmaceutical preparation including hard capsules, soft capsules, powders, granules, tablets, suspensions, and pills. The reference further specifies that the auxiliary materials used in the preparation of the medicine include corn starch, pregelatinized corn starch, hydroxypropyl methyl cellulose, sucrose, sodium starch glycolate, talc, magnesium stearate, soy lecithin, polyvinyl alcohol , Xanthan gum, titanium dioxide and pigments (para. 7-8, Summary of invention). These collectively teach a pharmaceutical composition formulated into a dosage form, reading on instant claims 17 and 21.
Haffizulla teaches that treatment with nitazoxanide 600 mg twice daily for 5 days was associated with a reduction of the duration of symptoms in participants with acute uncomplicated influenza (Interpretation, pg. 609), reading on instant claims 24-26. Nitazoxanide was given orally (pg. 617, left col, final para.), reading on instant claim 23. The study used a new controlled-release formulation of nitazoxanide designed to deliver the blood and to the respiratory tract and to maintain blood concentrations for 12 h (pg. 616, right col., second full para), reading on instant claim 22. The reference also teaches primary and secondary endpoints for the clinical trial. Secondary endpoints were change in influenza virus titre with time, time to cessation of viral shedding, time to alleviation of individual symptoms, symptom severity, complications of influenza, time to return to normal activity, time lost from work, and influenza antibody response (pg. 611 final para.- 612 first para.), reading on instant claims 27 and 28.
Pharmaceutics teaches that modified or controlled release drug delivery systems can be further classified as delayed or extended release (pg. 7, left column, first full para.). Extended-release products are formulated to make the drug available over an extended period after ingestion. This allows a reduction in dosing frequency compared to a drug presented as a conventional dosage form (pg. 8, left column), reading on instant claim 22.
Ascertaining the differences between the prior art and the claims at issue:
Reyoung does not specifically disclose the pharmaceutical composition being a pharamaceutically acceptable salt, nor does it provide specific information such as the dosage amount, dosage frequency, or treatment duration.
Haffizulla does not disclose a treatment of coronavirus caused illness.
Pharmaceutics does not teach a specific pharmaceutical composition or its use in the treatment of coronavirus caused illness.
Resolving the level of ordinary skill in the pertinent art:
Those of relevant skill in the art are those with the level of skill of the inventors of the references cited to support the Examiner’s positions.
Considering objective evidence present in the application indicating obviousness or nonobviousness:
The artisan would have recognized that the dosage forms disclosed in Reyoung (e.g. tablets, capsules, suspensions) are pharmaceutical compositions comprising nitazoxanide suitable for administration to patients. The artisan would have been motivated to employ these compositions in the treatment of viral illness caused by coronaviruses because Reyoung expressly teaches their use for coronavirus associated ILD. In view of prior clinical studies of nitazoxanide for influenza, which established effective dosage amounts, twice-daily dose administration, and a 5-day treatment duration, the artisan would have been motivated to adapt that regimen to the treatment of a coronavirus caused viral illness. It would have been obvious to do so because both influenza viruses and coronaviruses are respiratory pathogens treated with antivirals. Additionally, because effective antiviral treatment of coronavirus illness would be expected to shorten the time to return to normal health and the performance of normal daily activities, these clinical endpoints would have further motivated the artisan to apply the regimen. The artisan would also have recognized that the controlled-release nitazoxanide tablet described in Haffizulla is an extended-release composition, as it delivers the drug over a 12 hour period. It would have been obvious to incorporate such an extended release dosage form into the method for treating coronavirus illness, with the expectation that maintaining drug availability over an extended period would reduce dosing frequency and improve patient compliance while preserving therapeutic antiviral exposure.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONNOR KENNEDY ENGLISH whose telephone number is (571)270-0813. The examiner can normally be reached Monday Friday, 8 a.m. 5 p.m. ET..
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/C.K.E./
Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625