DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. 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.
Current Status of 18/717,914
3. This Office Action is responsive to the amended claims of 7 June 2024.
4. The amended claims 11-29 have been examined on the merits. Claims 11-29 are new.
Priority
5. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
6. The effective filing date is 11/17/2022.
Information Disclosure Statement
7. The information disclosure statements (IDS) submitted on 6/7/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
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.
8. Claims 11-29 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 11 cites the limitation of X1, X2 and X3, X4 wherein alkylene spaced by one or more (highlighted in yellow). It is unclear if the substituting moiety is placed before or after the alkylene referred to. That makes the claim confusing at least.
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9. Claims 26-29 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.
In claim 26, both “method” and “in the preparation of a medicament” are cited. It’s unclear what the claim is intending. It says it’s a method, but preparation of a medicament is a different statutory invention. Are they intending it to be administering a pharmaceutical composition? It causes a confusion, and the artisan would not know what indention of the claim, thereby rendering claim 26 and its dependent claims 27-29 indefinite.
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.
10. Claims 11-29 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 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.
In the instant claim 11, prodrug is cited, however prodrug forms are not known and thus the skill in the art as to what constitutes a prodrug form is beyond that of the artisan. The artisan understands that prodrug forms are generally determined a posteriori, and it is only through trial and error that prodrugs are identified. The artisan understands the concept of prodrugs, however the artisan does not per se understand what specifically describes a specific prodrug form. The art acknowledges there is no specific definition for prodrug (e.g. page 1, H.-K. HAN. AAPS Pharmsci. (2000) 2(1), article 6, pages 1-11), but that in general, the 'prodrug' is an inactivated form of the drug that activates in vivo to the active form. While some prodrugs are simply esters or salts, other prodrug forms are not chemically or structurally related to their active form, one example being glucose as the prodrug form of hydrogen peroxide (Table 1, page 5), as is hypoxanthine, thus posing a problem as to understanding what is the exact prodrug form of a compound, as hydrogen peroxide has two prodrug forms in the limited set of compounds exemplified in Han.
ETTMAYER (Ettmayer P. et al. J. Med. Chem. (2004) 47(10), pages 2393-2404), prodrugs are often accidental discoveries and TESTA (Testa B. Biochem. Pharm. (2004) 68, pages 2097-2106) teaches that, “A number of challenges await medicinal chemists and biochemists carrying out prodrug research, such as the additional work involved in synthesis, physicochemical profiling, pharmacokinetic profiling and toxicological assessment. Two of these challenges are introduced here, namely biological variability and toxicity potential. The challenge of biological variety results principally but not only from the huge number and evolutionary diversity of enzymes involved in xenobiotic metabolism. Inter- and intra-species differences in the nature of these enzymes, as well as many other differences such as the nature and level of transporters, may render prodrug optimization difficult to predict and achieve.” (page 2098).
The specification and claims provides the CBD derivatives, as does the prior art, however the specification briefly mentions prodrugs and is absent any examples of prodrugs that are contemplated. Additionally, the compound must function as a prodrug and that the active drug form must function as claimed, however the specification fails to provide any exemplary prodrug forms. Methods of making compounds, in general, are known to the artisan, however the methods of making any specific prodrug are complex and poorly understood, requiring an undue amount of experimentation to determine if a compound is actually a prodrug, and the instant specification fails to provide guidance to overcome the complexity and difficulties known to the artisan, as discussed.
The description requirement of the patent statue above requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”) Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
11. Claims 26-29 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification and prior art, while being enabling for treating nervous system disease, cancer, autoimmune disease, cardiovascular disease, pain, and inflammation disease, but does not reasonably provide enablement for preventing and/or treating nervous system disease, cancer, autoimmune disease, cardiovascular disease, pain, and inflammation disease cited in claim 26 . The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to the invention commensurate in scope with these claims.
The Wands Factors used in an (scope of) enablement rejection include (per MPEP 2164.01(a)):
1. The breadth of the claims:
The broadest reasonable interpretation (BRI) of instant claim 26 is drawn to a method for preventing and/or treating a disease of nervous system disease, cancer, autoimmune disease, cardiovascular disease, pain, inflammation disease, and liver injury by administering the compound of structure (I) in claim 11, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug or the solvate thereof. In addition, liver injury cited in the claim 26 is not a disease as claimed.
2. The Nature of the Invention:
The invention belongs to medicinals, more specifically, the administration of compounds of structure (I) in claim 11 to patients. The BRI of instant claim 26 defines the scope of diseases of nervous system disease, cancer, autoimmune disease, cardiovascular disease, pain, and inflammation disease.
3. The state of the prior art:
Recent status and prior art of CBD and CBD derivatives on treating diseases:
Therapeutic Efficacy of Cannabidiol (CBD): A Review of the Evidence from Clinical Trials and Human Laboratory Studies Curr Addict Rep. 2020 Jul 25;7(3):405–412.
Human laboratory studies and clinical trials (e.g., randomized controlled trials and single-arm, open label trials) evaluating the efficacy of CBD as a therapeutic were identified for various medical conditions, including epilepsy, anxiety, pain/inflammation, schizophrenia, various substance use disorders, post-traumatic stress disorder, and others. There is clear evidence supporting the utility of CBD to treat epilepsy. For other health conditions reviewed, evidence was often mixed and/or there was a general lack of well-powered randomized, placebo-controlled studies to draw definitive conclusions.
Cannabidiol and Other Cannabinoids in Demyelinating Diseases. Int. J. Mol. Sci. 2021, 22(6), 2992.
A growing body of preclinical evidence indicates that certain cannabinoids, including cannabidiol (CBD) and synthetic derivatives, may play a role in the myelinating processes and are promising small molecules to be developed as drug candidates for management of demyelinating diseases such as multiple sclerosis (MS), stroke and traumatic brain injury (TBI), which are three of the most prevalent demyelinating disorders. Thanks to the properties described for CBD and its interesting profile in humans, both the phytocannabinoid and derivatives could be considered as potential candidates for clinical use. This review summarizes current advances in the use of CBD and other cannabinoids as future potential treatments. While new research is accelerating the process for the generation of novel drug candidates and identification of druggable targets, the collaboration of key players such as basic researchers, clinicians and pharmaceutical companies is required to bring novel therapies to the patients.
Cannabis for the Treatment of Epilepsy: an Update. Current Neurology and Neuroscience Reports (2018) 18: 73.
Understanding of CBD’s efficacy and safety in the treatment of refractory epilepsy (TRE) has expanded significantly in the last few years. Future controlled studies of various ratios of CBD and THC are needed as there could be further therapeutic potential of these compounds for patients with epilepsy.
However, nothing in the prior art or recent status supports preventing a disease or any diseases of claim 26 by administration of compound of structure (I) of claim 11, especially for prevention of cancer and Alzheimer’s disease, etc., it is unknown and it can’t be done at time being.
4. The Level of one of ordinary skill:
The level of one of ordinary skill includes the knowledge/skill to engage in a reasonable amount of experimentation to make and use the pharmaceutical compositions underlying the instant method claims. The level of one of ordinary skill also includes knowledge in using small compounds to treat nervous system disease, cancer, autoimmune disease, cardiovascular disease, pain, and inflammation disease. However, no one has skill to engage in the undue burdensome level of experimentation required to provide guidance/ enablement for treating or preventing the diseases of the instant method claim 26.
5. The level of predictability in the art:
The art is predictable to make the instantly claimed pharmaceutical compositions. However, the art does not provide predictability as to which diseases and disorders can be prevented. To generate this level of guidance, one has to engage in undue burdensome experimentation (since no predictability in the art) to test the pharmaceutical composition against every disease cited in claim 26 to determine if the pharmaceutical composition can treat and/or prevent said disease(s). This level of experimentation would be required to match the scope of instant claim 26.
6-7. The amount of direction provided by the inventor and the existence of working examples
While the Specification teaches the results for the behavioral balance beam score of the model of Parkinson's disease (Table 17, Fig. 10), the content of dopamine in striatum of the model of Parkinson's disease after treatment (Table 18, Fig. 11), determining the positive rate of tyrosine hydroxylase (TH) cells in substantia nigra (SubN) by immunohistochemistry (Tables 12 and 13), and other assay methods, and subsequent statistical analysis of the effectiveness of the compounds. However, it does not teach how to prevent the assay-related disease, or provide direction for preventing the diseases per the BRI of instant claim 26.
8. The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
The scope of diseases per the BRI of instant claim 26 would require an undue amount of experimentation to use the invention as claimed to treat and/or prevent diseases of nervous system disease, cancer, autoimmune disease, cardiovascular disease, pain, and inflammation disease with compounds of structure (I) in claim 11. Moreover, the amount of experimentation required to prevent any of the claim 26 diseases would be undue as well, absent evidence in the Specification or prior art.
Therefore, claim 26 and its dependent claims 27-29 are rejected under 35 USC 112(a) for lacking enablement for the scope of a method for preventing and/or treating a disease of nervous system disease, cancer, autoimmune disease, cardiovascular disease, pain, and inflammation disease with compounds of structure (I) in claim 11.
Claim Rejections - 35 USC § 103
12. 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.
13. Claim(s) 11-29 are rejected under 35 U.S.C. 103 as being unpatentable over JOHN (WO2021062231A2, pub date: 4/1/2021. Referenced in IDS of 6/7 /2024 and provided by Applicants) in view of VALE (Vale et al. “Amino Acids in the Development of Prodrugs” Molecules 2018, 23, 2318), further in view of KARANEWSKY (WO200023421A1).
Determining the scope and contents of the prior art
JOHN teaches cannabinoid (including cannabidiol (CBD)) prodrug compounds of Formula I that provide site specific delivery to an area of interest. The prodrug compounds overcome deficiencies in the physicochemical properties of CBD that limit formulation options while enhancing delivery of CBD to a target site of interest. In addition, key pharmaceutical properties including solubility, permeability or partitioning, chemical or enzymatic stability and transporter affinities can be improved (para [0006]).
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The prodrug compounds of Formula I are mono-substituted phenol derivatives with a variety of side chains of carbamates, carbonates, ethers and esters (see above. Formula X-a to Formula X-e, para [0007]). It is worth noting that the C terminal of the amino acid residue is linked to the phenol ring of CBD in Formula X-c.
JOHN further teaches a pharmaceutical composition comprising a therapeutically effective amount of the compounds (claim 12, p 44) and a method of treating cancer and other disease associated with GPR55 (para [0031]-[0032], p 9-10) in a subject comprising administering to the subject a therapeutically effective amount of the compounds (claim 19, p 45). The pharmaceutical composition may also contain one or more physiologically acceptable surface, active agents, additional carriers, diluents, excipients, smoothing agents, suspension agents, film forming substances, and coating assistants, or a combination thereof (para [0060], p 22).
JOHN teaches G-protein coupled receptors are active in many biologic and neurologic events including, but not limited to: addiction, anxiety, appetite, nausea, pain, sleep, vomiting … (para [0031], p 9), and may be used for treating a variety of diseases including inflammatory pain, …neuropathic pain, …, pain, chronic pain, …, rheumatoid arthritis pain, osteoarthritic pain, back pain, cancer pain, dental pain, muscular pain, …, inflammation, neurodegenerative disease, cough, broncho-constriction, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colitis, cerebrovascular ischemia, emesis such as cancer chemotherapy-induced emesis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, asthma, dermatitis, gastroesophageal reflux disease (GERD), constipation, diarrhea, functional gastrointestinal disorders, irritable bowel syndrome, cutaneous T cell lymphoma, multiple sclerosis, osteoarthritis, psoriasis, systemic lupus erythematosus, diabetes, glaucoma, osteoporosis, glomerulonephritis, renal ischemia, nephritis, …, adult respiratory disease syndrome, chronic obstructive pulmonary disease (COPD), cryptogenic fibrosing alveolitis, and bronchitis (para [0032], p 9).
VALE teaches amino acid prodrugs have a proven track of improving several pharmacological parameters, such as oral bioavailability of drugs that have poor solubility and permeability. Amino acid prodrugs have successfully been used to achieve sustained release, intravenous delivery, and improved metabolic stability. Moreover, amino acid promoieties have been described as an important tool to enhance the transposition of the blood-barrier brain, which is important for several central nervous diseases that have few drugs available to combat them. In addition, these promoieties are safe pharmacological agents and do not increase the toxicity of compounds but might alleviate side effects of most drugs, especially those used as anticancer agents (page 50 of 61).
KARANEWSKY teaches attaching the N terminal of an amino acid ester (or other nucleophiles) to a phenol by using methyl bromoacetate (Example 5, Part A and Part B, p 55) summarized below:
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Ascertaining the differences between the prior art and the claims at issue
The instant claims are generally drawn to preparation, compositions of cannabidiol (CBD) derivatives (including both mono- and di-substituted CBDs) for treatment of diseases.
JOHN teaches compounds of Formula I of mono-substituted CBD derivatives, compositions and methods for treating disease, but JOHN does not teach di-substituted CBD derivatives encompassed in the instant claims.
It is noted that the preparation of both mono- and di-substituted CBDs requires the same technique as indicated in the Specification. As for di-substituted CBDs, like their mono-CBD counterparts, they may further overcome deficiencies in the physicochemical properties of CBD and key pharmaceutical properties including solubility, permeability or partitioning, chemical or enzymatic stability and transporter affinities as taught by JOHN (para [0006]).
Additionally, JOHN teaches connecting an amino acid residue (Formula X-c) to the OH group of CBD by esterification using the C terminal of the amino acid, but JOHN does not teach connecting an amino acid residue and a CBD molecule through the N terminal of the amino acid.
VALE teaches amino acid prodrugs can improve pharmacological parameters, such as oral bioavailability of drugs that have poor solubility and permeability, achieve sustained release, intravenous delivery, and improved metabolic stability, enhance the transposition of the blood-barrier brain. In addition, these promoieties are safe pharmacological agents and do not increase the toxicity of compounds (page 50 of 61).
KARANEWSKY teaches connecting the OH group of a phenol and the N terminal of an amino acid through the reactions involving methyl(t-butyl) bromoacetate, which cures the defect of JOHN’s teaching on connecting an amino acid to a CBD molecule.
Considering Objective Evidence Present in the Application Indicating
Obviousness or Nonobviousness
Regarding claims 11-22, the artisan would be motivated to modify JOHN’s and VALE’s teachings by adding methyl bromoacetate to the reactions to link the N terminal of an amino acid residue to a phenol ring taught by KARANEWSKY to reach the instant claims. The structures in claim 22 come from L-methionine methyl ester (the two left molecules) and L-methionine (the two right ones). It should be pointed out that the same art of synthesis is used for both mono and double substitution of the OH groups of CBD molecule. The artisan would be motivated to make such modifications to enhance delivery of CBD to a target site of interest by increasing solubility, permeability or partitioning, chemical or enzymatic stability taught by JOHN (para [0006]) and similar beneficial effects of amino acid prodrugs taught by VALE (see above, page 50 of 61) for both mono- and bi-substituted CBD derivatives/prodrugs with amino acid. Thus, claims 11-22 are obvious over JOHN in view of VALE and KARANEWSKY.
Regarding claims 23 and 24, the combination of JONN, VALE and KARANEWSKY teaches the ‘flat’ structures in claims 11 and 22 which embrace all isomers, and since there are so few alternatives and they are necessarily inherent. In the molecules, the two chiral centers on the cyclohexene ring come from and are inherent to the original CBD molecule and new chiral center(s) is/are from the natural amino acid/ester attached (L-methionine in claims 22 and 24 and its ester in claim 22) and also inherent. Claim 11 anticipates claim 23 and claim 22 anticipates claim 24. Therefore, claims 23 and 24 are obvious over JOHN in view of KARANEWSKY and VALE.
Regarding claims 25 and 26-29 directed to a pharmaceutical composition and one or more pharmaceutically acceptable excipients, and method of treating a variety of diseases, it would have been obvious to have used the compound of the CBD-amino acid prodrugs in the methods because it would have provided the beneficial effects of both CBD prodrugs taught by JOHN and amino acid prodrugs taught by VALE (see above). JOHN’s teaching on treating diseases is shown above (paras [0031]- [0032], p 9). Thus, claims 25, 26-29 are obvious over the combination of JOHN, VALE and KARANEWSKY.
Conclusion
14. No claims are presently allowable as written.
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/B.T./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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