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 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 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 the compounds, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts thereof claimed herein, does not reasonably provide enablement for a metabolite or prodrug. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
Undue experimentation is a conclusion reached by weighing the noted factual considerations set forth below as seen in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). A conclusion of lack of enablement means that, based on the evidence regarding a fair evaluation of an appropriate combination of the factors below, 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.
These factors include:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on
the content of the disclosure.
The breadth of the claims - The nature of the invention
The claims are drawn to compounds of claim 1, or stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, metabolites, or prodrugs thereof. The breadth of the claims includes all of the hundreds of thousands of compounds of formula of claim 1 as well as the presently unknown list potential metabolites and prodrug derivatives embraced by claim.
The nature of the invention is clinical use of compounds and the pharmacokinetic behavior of substances in the human body.
The state of the prior art
Finding a prodrug is an empirical exercise. Predicting if a certain ester of a claimed alcohol, for example, is in fact a prodrug, that produces the active compound metabolically, in man, at a therapeutic concentration and at a useful rate is filled with experimental uncertainty. Although attempts have been made to predict drug metabolism de novo, this is still an experimental science. For a compound to be a prodrug, it must meet three tests. It must itself be biologically inactive. It must be metabolized to a second substance in a human at a rate and to an extent to produce that second substance at a physiologically meaningful concentration. Thirdly, that second substance must be biologically active. Determining whether a particular compound meets these three criteria in a clinical trial setting requires a large quantity of experimentation. Wolff (Medicinal Chemistry) summarizes the state of the prodrug art. (Wolff, Manfred E. "Burger's Medicinal Chemistry, 5ed, Part I", John Wiley & Sons, 1995, pages 975-977.) The table on the left side of page 976 outlines the research program to be undertaken to find a prodrug. The second paragraph in section 10 and the paragraph spanning pages 976-977 indicate the low expectation of success. In that paragraph the difficulties of extrapolating between species are further developed. Since, the prodrug concept is a pharmacokinetic issue, the lack of any standard pharmacokinetic protocol discussed in the last sentence of this paragraph is particularly relevant. Banker (Modern Pharmaceutics) (Banker, G.S. et al, "Modern Pharmaceutics, 3ed.", Marcel Dekker, New York, 1996, page 596) in the first sentence, third paragraph on page 596 states that “extensive development must be undertaken” to find a prodrug. Wolff (Medicinal Chemistry) in the last paragraph on page 975 describes the artisans making Applicants' prodrugs as a collaborative team of synthetic pharmaceutical chemists and metabolism experts. Likewise, regarding “metabolites” – these are the compounds which are produced after the compounds of formula I are administered. The art is silent as to what these compounds would produce upon administration in vivo.
The amount of direction provided by the inventor
The instant specification is not seen to provide adequate guidance which would allow the skilled artisan to extrapolate from the disclosure and examples provided to make or use the claimed compounds commensurate in the scope with the instant claims. There is a lack of data and examples which adequately represent the claims as written. The examiner notes, there has not been provided sufficient instruction or sufficient methodological procedures to support the prodrugs and metabolites instantly claimed.
The existence of working examples
There are no working examples of a prodrug or metabolite of any compound.
The quantity of experimentation needed to make and use the invention based on the content of the disclosure
It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved", and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Thus, undue experimentation will be required to determine if any particular compound of claim 1 is, in fact, a prodrug or metabolite of the compound of formula I. Since the structures of these “prodrugs” and “metabolites” are uncertain, direction for their preparation must also be unclear. Directions to a team of synthetic pharmaceutical chemists and metabolism experts of how to search for a "prodrug" or “metabolite” hardly constitute instructions to the BS process chemist of how to make such a compound.
Claims 11-12 and 15-16 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 treating COVID-19, influenza A, and influenza B infections caused by infections of viruses in host cells (as in claim 11), or treating pulmonary thrombosis (as in claim 15), does not reasonably provide enablement for treating any disease caused by infection of any virus; nor prevention of any claimed disease as in claim 11 or 15. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
Undue experimentation is a conclusion reached by weighing the noted factual considerations set forth below as seen in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). A conclusion of lack of enablement means that, based on the evidence regarding a fair evaluation of an appropriate combination of the factors below, 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.
These factors include:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on
the content of the disclosure.
The breadth of the claims/Nature of the Invention:
The claims are drawn to methods of treating or preventing all viral disease wherein the viruses have spike proteins and treating or preventing pulmonary thrombosis. In the absence of an explicit definition in Applicant's specification, "Prevention" as recited in the instant claims, is interpreted to mean the complete and total blocking of all symptoms of a disorder for an indefinite period of time. Any therapy which merely reduces the number or severity of symptoms, or which is effective for a period shorter than the subject's remaining lifespan, is considered to be ineffective at preventing a disorder.
The state of the prior art:
Prevention of any disorder in the sense being used herein is not a recognized clinical outcome in the art.
The level of predictability in the art:
Regarding prevention, prevention of a disease is not the same as treatment of said disease. In order to prevent a disease, as opposed to merely delaying or reducing its symptoms, a dosing must either render the subject completely resistant to said disease after a single treatment or a limited number of treatments, or else, when continued indefinitely, continue to completely suppress the occurrence of said disease. In order to practice a preventative method, one of skill in the art must know the answer to several questions in addition to the effectiveness of the therapy in short-term relief of symptoms, including: 1) What is the duration of a single course of therapy? How often must the therapy be administered to completely suppress the disease? 2) Does the subject develop tolerance to the therapy over time? Does the disease eventually progress to a point where the therapy is unable to completely suppress all symptoms? For example, will a metastatic cancer eventually adapt to overcome treatments directed to preventing it from metastasizing into the bone? Or will a case of osteoporosis or rheumatoid arthritis ultimately progress to a point where symptoms develop regardless of which therapy is administered. 3) What are the long-term effects of the therapy? Does it cause progressive damage to the kidneys, liver, or other organs? Does the active agent accumulate in the subject's tissues? Is the minimum dose necessary to completely prevent the disease safe for long-term administration? Are there any steps that can be taken to reduce side effects? Additionally, because various physiological systems are interdependent and affect one another, any hypothetical preventative treatment would have to be broad-based and treat all of the various causes of a disorder. For example, because osteoporosis is, in the majority of cases, caused at least in part by a reduction in estrogen levels, a true preventative treatment for osteoporosis must be capable of preventing or reversing menopause in a subject. For this reason, many therapies which are suitable for short-term relief of symptoms are not suitable for lifelong prevention of disease. For example, antibiotics, chemotherapeutics, and antiviral drugs are not normally administered to healthy subjects in order to prevent the development of infection or cancer. Furthermore, a tissue can degenerate for a variety of reasons, including but not limited to, exposure to toxins, chronic viral infection, autoimmune attack, and deposition of amyloid protein. To be fully successful, a preventative method would have to guard against all of these possible insults.
The amount of direction provided by the inventor:
Applicant's specification discloses assays by which the coronavirus inhibitory activity and anticoagulation activity of various compounds can be determined. No guidance is given in the specification suggesting any reason to believe that administration the claimed compounds can completely prevent all of the claimed conditions.
The existence of working examples:
No working examples are given for the treatment or prevention of any disease. Note that lack of working examples is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art such as the treatment of broad categories of disease with a single agent. See MPEP 2164.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
As mentioned above, the short-term usefulness of a therapy for relief of symptoms is no guarantee of its long-term usefulness for prevention of disease. Because no guidance is given for the use of the claimed therapeutic method for the long-term prevention of disease, one skilled in the art wishing to practice the invention would be unable to do so without first gathering information as to the long-term effectiveness of the therapy. In particular, one skilled in the art, in order to practice the invention for prevention of disease, would need to know whether the preventative effect remains potent over the long term. In order to answer these questions in the absence of any existing data, one skilled in the art, in order to practice the invention, would undertake long-term animal tests, preferably over a period of years, preferably involving a relatively long-lived experimental animal such as dogs or monkeys, or a human clinical trial. Animal experiments include, along with induction of the disease state, administration of the potential pharmaceutical compound and collection and analysis of data, additional burdens associated with compliance with animal welfare regulations, care, feeding, and other maintenance of the animals, dissection of dead animals to collect data, and disposal of dead animals after the protocol is finished. Administering the claimed compounds for a period of years to a suitable subject population is an undue amount of experimentation needed in order to practice the full range of the claimed invention. As prevention in the full sense is an extremely high bar for any clinical outcome, there is no reason to believe that the therapy would be successful, and any actual success would be a surprising and unpredictable result.
Claims 1-7 and 9-16 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 claim(s) 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. This is a written description rejection.
The claims of the instant application are drawn to a compound of formula R(X)n where R is a monosaccharide or aromatic ring and X is -QC(O)-R’((X’)m). Q is O, N, or SO2; R’ is an optionally substituted six-membered aromatic ring, coumarin, isocoumarin, flavone, isoflavone, or glucosamine; and X’ is QH or QC(O)-monosaccharide. As such, the scope embraced by the present compounds includes tens of thousands of compounds. Some being having a single saccharide unit, some having multiple, some having none. The rings can be linked via numerous groups at any position on the core and the only common feature required among all compounds is the C(O) group in Q. Likewise, the “optionally substituted six-membered aromatic rings” of R’ include thousands of compounds by themselves. However, applicants have only made the specific compounds of claim 8 herein which all comprise either a six-membered aromatic ring, monosaccharide, isocoumarin, or isoflavone as R. The only Q linking group used was O. The only R’-groups made are six-membered aryl groups substituted with three hydroxy groups. The showing of that which was made is not representative of the scope of that being claimed.
The support in the specification is not adequate for the claims to the broad genus comprising the various and diverse moieties intended to be part of the chemical claimed. The data presented shows very limited synthetic variation to the chemical core and this does not correlate via art recognized evidence or adequate support in the instant disclosure for claiming such a broad, variable genus. An adequate representation of a species requires that the species which are expressly described are recognized in the art as representative of the entire genus. Currently, one of skill in the art would not recognize the described compounds which comprise the limited variation of groups as disclosed herein as representative of the entire genus as claimed, and therefore, applicants did not have possession of the entire genus as claimed, but only the species.
It is noted that a single species is seldom, if ever, sufficient to support a generic claim. See In re Shokal, 242 F.2d 771, 113 USPQ 283, 285 (CCPA 1957). See also, In re Grimme, 274, F.2d 949, 124 USPQ 499, 501 (CCPA 1960).
While there more than 1 species made, these species all embrace very limited overlap that would expand to the entirety of that being claimed.
Claim Rejections - 35 USC § 112
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 1-16 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 1 is drawn to a compound having at least one basic unit R(X)n. This R(X)n formula is the main structure of the claim. Thus it is unclear what is intended by this recitation as how can a compound have multiple compounds?
Claim 1 is indefinite as the claim provides R is a monosaccharide or derivative thereof. In the absence of the identity of moieties intended to modify an art recognized chemical core, described structurally or by chemical name, the identity of a derivative would be difficult to ascertain. In the absence of said moieties, the claims containing the term “derivative” are not described particularly sufficiently to distinctly point out that which applicant intends as the invention.
Claim 1 is indefinite wherein R is a monosaccharide or aromatic ring, wherein at least one of the monosaccharide and aromatic ring is optionally substituted with at least one substituent selected from amino and carboxyl. This recitation of at least one of them is optionally substituted is confusing and the phrase “at least one of” appears unnecessary.
Claim 1 is indefinite as the claims defines Q as optionally being N. However, this would leave a charged radical and the examiner believes this should be an NH and not an N.
Claim 2 is indefinite wherein it is unclear as to what applicants are claiming. As noted above, it is unclear as to how the compound can have a plurality of compounds. Likewise, the claimed linkage and description of recursive hierarchy is confusing. Clarity is requested as to what is intended.
Claim 3 is indefinite wherein it is unclear as to what applicants are claiming. As noted above, it is unclear as to how the compound can have a plurality of compounds. Likewise, the claimed linkage and description of recursive hierarchy is confusing. Clarity is requested as to what is intended.
Claim 4 is indefinite as the claim provides R is a monosaccharide or derivative thereof. In the absence of the identity of moieties intended to modify an art recognized chemical core, described structurally or by chemical name, the identity of a derivative would be difficult to ascertain. In the absence of said moieties, the claims containing the term “derivative” are not described particularly sufficiently to distinctly point out that which applicant intends as the invention.
Claim 4 is indefinite as the claims defines Q as optionally being N. However, this would leave a charged radical and the examiner believes this should be an NH and not an N.
Claim 8 is indefinite wherein the claim is “selected from the following structures” and lists 7 compounds without an “and” or “or” to close the group. Applicants should use standard Markush language such as “the compound is selected from the group consisting of … and…”.
Claim 10 is indefinite wherein the claim provides the composition is one of various forms, “preferably nasal sprays”. It is unclear if applicants intend only nasal sprays, or an of the previous forms also.
Claim 12 is indefinite wherein the claim provides the composition is one of various forms, “preferably nasal sprays”. It is unclear if applicants intend only nasal sprays, or an of the previous forms also.
Claim 14 is indefinite wherein the claim provides the composition is one of various forms, “preferably nasal sprays”. It is unclear if applicants intend only nasal sprays, or an of the previous forms also.
Claim 16 is indefinite wherein the claim provides the composition is one of various forms, “preferably nasal sprays”. It is unclear if applicants intend only nasal sprays, or an of the previous forms also.
All claims which depend from an indefinite claim are also indefinite. Ex parte Cordova, 10 U.S.P.Q. 2d 1949, 1952 (P.T.O. Bd. App. 1989).
Claim Rejections - 35 USC § 102
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 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) 1-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 9,120,744.
‘744 discloses the compound:
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in column 30 which would anticipate the compound 1 of claim 8 herein having the structure:
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. The compounds reads on the present variables of claim 1 wherein R is an aromatic ring phenyl; n is 2; Q is O; R’ is a six-membered aromatic ring; X’ is QH where Q is O and m is 3. It is noted that that are numerous compounds in ‘744 which would anticipate the present compounds (see also at least CXVI in column 61).
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.
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.
Claim(s) 1-10 and 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over US 9,120,744.
The claims of the present application are drawn to compounds of claim 1; pharmaceutical compositions comprising the same; and methods of treating pulmonary thrombosis with the same.
‘744 discloses the compound having the formula:
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which anticipate the present compounds as set forth supra. ‘744 teaches their compounds are effective PAI-1 inhibitor compounds and are effective in treating pulmonary thrombosis (see column 7, line 34-35) and various diseases related to elevated vitamin K levels. The compounds are taught to be in various forms of a composition (see column 126) thus rendering obvious pharmaceutical compositions comprising the same. What is not taught is to administer the compounds to reduce vitamin K level or treat the pulmonary thrombosis.
It would have been obvious to one of skill in the art to formulate a compositions of the compounds of ‘744 and administer the same reduce vitamin K or to treat pulmonary thrombosis as these are directly taught and suggested therein.
Claim(s) 1-12 are is/are rejected under 35 U.S.C. 103 as being unpatentable over US 9,120,744 as applied to claims 1-8 above, and further in view of US 2023/0355605.
The claims of the present application are drawn to compounds of claim 1; pharmaceutical compositions comprising the same; and methods of treating viral diseases with the same.
‘744 discloses the compound having the formula:
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which anticipate the present compounds as set forth supra. ‘744 teaches their compounds are effective PAI-1 inhibitor compounds thus rendering obvious pharmaceutical compositions comprising the same. What is not taught is to treat viral diseases.
US 2023/0355605 teaches that PAI-1 inhibitors and their fibrinolytic enhancing effect are expected to suppress hypercoagulability and pulmonary fibrosis in COVID-19 patients and thus suppress ARDS. See [0154]-[0158].
As such, it would have been obvious to use the PAI-1 inhibiting compounds of ‘744 to treat a coronavirus infection as ‘605 teaches this class of compounds effectively treat the disease.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TRAVISS C MCINTOSH III whose telephone number is (571)272-0657. The examiner can normally be reached Monday-Friday 9AM-5:30PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Goon can be reached at 571-270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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TRAVISS C. MCINTOSH III
Primary Examiner
Art Unit 1693
/TRAVISS C MCINTOSH III/ Primary Examiner, Art Unit 1693