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 .
Priority
This application is a 371 of PCT/GB2022/051198 (05/11/2022)
and claims foreign priority to UNITED KINGDOM 2106789.7 (05/12/2021).
Status
Claim rejections not reiterated are withdrawn.
Claims 1, 3-5, 23-30 are pending.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 1 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature (law of nature or natural phenomenon) without significantly more. Subject matter eligibility guidance from MPEP 2106 requires considering the following steps:
Step 1: the claims are to a chemical compound of 6-OH-CBD-C4 product. (Step 1: Yes).
Step 2A, prong one: 6-OH-CBD-C4 is a nature-based product because it is a naturally occurring metabolite as evidenced by the instant specification [0014] and Li et al. (European Journal of Medicinal Chemistry 192 (2020) 112163, 14 pages, p. 5-6, Table 3, analogous Compound Nos. 13 and 32, “Natural compound” and “Metabolite”, “metabolites produced by human liver microsomes”), thus the markedly different characteristics analysis is used to determine if the nature-based product is a product of nature exception. MPEP 2106.04(c)(I). The compound of the claims is a metabolite that occurs in a human. Therefore, the naturally occurring counterpart is the compound as it occurs in nature inside a human. Upon comparing the claimed product to the naturally occurring counterpart the comparison shows there are no differences in chemical structure or any other aspect or characteristic.
Step 2A, prong two: This part of the eligibility analysis evaluates whether the claim as a whole integrates the recited judicial exception into a practical application of the exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application. The claims do not recite language which integrates the exception into a practical application. Even in claim 2, the pure compound is identical to the compound as it occurs in nature. (Step 2A: Yes).
This part of the eligibility analysis evaluates whether the claim as a whole amounts to
significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim. MPEP 2106.05. As discussed with respect to Step 2A Prong Two, the claim does not recite any additional element beyond the judicial exception. Thus, the claims lack an inventive concept (Step 2B: NO). The claim is not eligible.
Response to Remarks - 35 USC § 101
Applicant argues that the claimed compound, 6-OH-CBD-C4, is not a naturally occurring metabolite because the compounds cited in the instant specification and Li are not the same compound.
This argument is not persuasive because the naturally occurring counterpart is the metabolized compound as it occurs in nature inside a human as established by the instant specification at [0014] which states that CBD-C4 is naturally occurring in the cannabis plant, and thus, when administered to humans as disclosed by Li would be metabolized in the same manner to form 6-OH-CBD-C4. This assertion is supported by Li’s teaching of “metabolites; (-)-6aOH-CBD/(-)-6bOH-CBD (13) results from C-6 hydroxylation. In addition, compounds 13 and 14 are (-)-CBD metabolites produced by human liver microsomes (HLMs), and CYP3A4 and CYP2C19 in HLMs play key roles in the formation of 6a-OH” (p. 5). Given the analogous relationship of CBD (having a C5 chain) and CBD-C4, differing by only by an alkylene, the same CYP3A4 and CYP2C19 in HLMs would metabolize the analogs in the same manner and necessarily result in formation of 6-OH-CBD-C4.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Li et al. (European Journal of Medicinal Chemistry 192 (2020) 112163, 14 pages).
Li teaches CBD-C4 is a component extracts of Cannabis administered to humans for treating seizures (p. 3, 5-6) which are then metabolized to form the 6-OH-CBD-C4 (p. 5-6, Table 3, analogous Compound Nos. 13 and 32, “Natural compound” and “Metabolite”, “metabolites produced by human liver microsomes”) and inherently anticipates claim 1.
Response to Remarks - 35 USC § 102
Applicant argues that the claimed compound, 6-OH-CBD-C4, is not the compound taught by Li.
This argument is not persuasive because as taught by Li, CBD-C4 is a component in the cannabis plant, and when administered to humans as disclosed by Li would be metabolized in the same manner to form 6-OH-CBD-C4. This assertion is supported by Li’s teaching of “metabolites; (-)-6aOH-CBD/(-)-6bOH-CBD (13) results from C-6 hydroxylation. In addition, compounds 13 and 14 are (-)-CBD metabolites produced by human liver microsomes (HLMs), and CYP3A4 and CYP2C19 in HLMs play key roles in the formation of 6a-OH” (p. 5). Given the analogous relationship of CBD (having a C5 chain) and CBD-C4, differing by only by an alkylene, the same CYP3A4 and CYP2C19 in HLMs would metabolize the analogs in the same manner and inherently result in formation of 6-OH-CBD-C4.
Claim Rejections - 35 USC § 103
When the reference discloses all the limitations of a claim except an inherent property or function, and the examiner cannot determine whether or not the reference inherently possesses properties which anticipate or render obvious the claimed invention but has basis for shifting the burden of proof to applicant as in In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980). See MPEP §§ 2112 - 2112.02.
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 1-5, 24-30 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (European Journal of Medicinal Chemistry 192 (2020) 112163, 14 pages) in view of Stott et al. (US20170209390), Morales et al. (Front. Pharmacol. 8:422, 18 pages) and Hampson et al. (US6630507).
Li reviews CDB analogs and their therapeutic utility, including modification on the terpene moiety and benzene ring (Abstract; p. 5-6). Li teaches 6-OH-CBD and 7-OH-CDB are metabolites of CBD and a believed to be responsible for the biological activity observed from CBD (p. 5: “Some of the biological effects observed are hypothesized to be due to active metabolites rather than (-)-CBD itself”). Li teaches CBD-3, -4, and -5 (Compound Nos. 31, 32, and 4; “C” alkyl chain length homologs) are analogs and natural compounds. Li also teaches the SAR of CBD and identifies the “C” alkyl chain as variable (Fig. 5):
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Regarding claim 1, Li’s teaching of 6-OH-CBD (compound 13) differs from the claim by the alkyl chain length or alternatively the 6-OH substitution of CBD-C4 (Li’s compound 32).
Stott teaches CBD, CBDV and metabolites “7-hydroxy-cannabidol (7-OH-CBD) and/or 7-hydroxy-cannabidivarin (7-OH-CBDV) in the treatment of epilepsy” with demonstrations in vivo (Abstract; [0023]; [0065]-[0069]; [0077]). Stott teaches the structures as (p. 3):
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.
Morales reviews the medicinal chemistry of CBD and derivatives and teaches 6-OH-CBD-triacetate has therapeutic potential as an anti-convulsant (Table 1). Morales teaches the following compound has in vivo anticonvulsant activity:
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(Fig. 12; p. 10: “the in vivo anticonvulsant activity of four diacetylated-CBD analogs (CBD-aldehyde-diacetate, 6-oxo-CBD-diacetate, 6-hydroxy-CBD-triacetate, and 9- hydroxy-CBD-triacetate, Figure 12) was demonstrated in a mouse model”). Morales teaches that the acetates are considered prodrugs of the hydroxyl and the 6-OH-CBD is the active form, analogous to the active 7-OH-CBD formed from CYP3A- and CYP2C- metabolism (p. 10).
Hampson teaches analogs of CBD useful for treating a wide range of diseases including species 6-OH-CBD (Example 11, p. 26 compound 46 and 47) as well as a genus of compounds of the formula
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including where R20 is OH, R19 is CH3, and R26 is alkyl (claims 11-13).
One of ordinary skill in the art of cannabinoids following the teaching of Li would have known that 6-OH-CBD was a biologically active compound potentially useful in treating epilepsy. One of ordinary skill in the art would have also known from Li based on the SAR studies that modifications to the alkyl chain would result in varying agonistic activity of the compound and in view of the teaching of Stoll that C3-alkyl and C5-alkyl compounds showed in vivo utility in treating epilepsy would have had a reasonable expectation of success in modifying the alkyl chain to C4. In addition, as taught by Hampson, the claimed invention is within Hampson genus and one of ordinary skill in the art would have considered the closely structurally related compounds with 6-OH and C4 as homologs and arrive at the claimed invention. Furthermore, one of ordinary skill in the art following the combined teaching in view of Morales would have known that 6-OH-CBD and the prodrug form was shown to have anticonvulsant activity. Thus, considering the teaching of the prior art as a whole all in the same field of cannabinoids provides a reasonable expectation of success in arriving at the claimed invention.
Additionally, because Li’s 6-OH-CBD is an alkyl homolog of the claimed invention and because the metabolized CBD-C4 is of the same structure, one of ordinary skill in the art would have had a presumed expectation that the claimed homologous compound would possess similar properties as disclosed by the prior art. As per MPEP 2144.09:
Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.).
Regarding claim 2-3, one of ordinary skill in the art formulating the compound as a pharmaceutical would have considered a pure, isolated, and synthetic compound in forming a pharmaceutical composition and arrive at the claimed invention.
Regarding claim 4-5, one of ordinary skill in the art would consider routine formulating a pharmaceutical compound as a tablet or suspension with conventional carriers and adjuvants and as specifically taught by Hampson (col 20) and arrive at the invention as claimed.
Regarding claim 24, Li (p. 8, 11) , Stott, and Morales all teach that CBD and derivatives are useful for treating epilepsy and one of ordinary skill in the art would have considered the compound for the same use and arrive at the claimed invention.
Regarding claim 25, Morales teaches CBD is useful for “treatment-resistant seizure disorders, including Lennox–Gastaut and Dravet syndromes” (p. 2) as does Stott ([0010]-[0012]: generalized seizures).
Regarding claims 26-27, Stott teaches combination of the CBD analog with AEDs including clobazam ([0034]-[0035]).
Regarding claims 28-30, Stott teaches dosing the CBD analog at preferably between 1 and 2000 mg, with embodiments at 200 mg ([0036], [0042]).
With each of the claims, the level of skill in the art is very high such that one of ordinary skill in the art would consider routine the combination of elements from the teaching of the art. One of ordinary skill in the art would have recognized that the results of the combination would be predictable due to the well-known nature and optimizations routinely performed in the art. Thus, one of ordinary skill in the art would have arrived at the invention as claimed before the effective filing date with a reasonable expectation of success.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (European Journal of Medicinal Chemistry 192 (2020) 112163, 14 pages) in view of Stott et al. (US20170209390), Morales et al. (Front. Pharmacol. 8:422, 18 pages) and Hampson et al. (US6630507) as applied to claims 1-5 above and further in view of Emmett (“Synthesis of 6 Hydroxy-8,9-dihydrocannabidiol”, Univ of Del, Ph.D. Thesis, 1973, 72 pages) and Lander et al. (J. Chem. Soc., Perkin Trans. 1, 1976, 8-16).
As per the 103 rejection supra, one of ordinary skill in the art would have been motivated to synthesize the obvious compound for use in a pharmaceutical composition, including via known techniques applied to homolog compounds such as 6-OH-CBD as taught by Emmett and Lander.
Emmett teaches synthesis of 6-OH-CDB by acylation using acetic anhydride in pyridine to CBD-diacetate (p. 39):
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;
oxidation to 6-OH-CBD-diacetate (p. 41):
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and reduction to 6-OH-CBD with LiAlH4 (p. 42):
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. Thus Emmett teaches the same steps but does not disclose the 6-oxo intermediate.
Lander teaches oxidation of CBD-diacetate with sodium chromate to 6-oxo-CBD-diacetate (p. 14), followed by reduction with LiAlH4, but does not disclose the initial acylation step as that was the starting material.
Regarding claim 23, one of ordinary skill in the art performing the synthesis of the obvious compound utilizing the Lander technique would have produced the 6-oxo-CBD-C4 compound and arrive at the claimed invention.
One of ordinary skill in the art would have considered routine the application of known synthetic techniques and apply them to an alkyl homolog with a reasonable expectation of success. These synthetic techniques, including the use of acetic anhydride, pyridine, and chromium were all used by the cited art are considered routine and well within one of ordinary skill in the art’s technical grasp such that the synthesis would have been obvious to one of ordinary skill in the art.
Response to Remarks - 35 USC § 103
Applicant argues Li does not identify 6-OH-CBD as a lead compound and thus one of ordinary skill in the art would not have considered it for modification and that there was no articulated reason to modify the lead compound.
This argument is not persuasive because Li specifically teaches 6-OH-CBD as a metabolite suggested to be responsible for the biological activity observed from CBD (p. 5: “Some of the biological effects observed are hypothesized to be due to active metabolites rather than (-)-CBD itself”). Combined with Li’s teaching of CBD-3, -4, and -5 with varying alkyl chain length as homologs and the SAR study of CBD identifying the “C” alkyl chain as important (Fig. 5) for inverse agonist activity alone would have suggested to one of ordinary skill in the art the compound 6-OH-CBD-C4. Regarding Li’s teaching of the importance of the alkyl chain length and shrinkage, Li also teaches how the chain length is shorter in other compounds, some of which are in clinical trials (p. 6-8, Fig. 6, Table 4, compound 31 C-3), thus one of ordinary skill in the art would have considered the chain length as “important” and a results-effective variable for optimization among homologs. In addition, Stott teaches 7-OH-CBD in the treatment of epilepsy” with demonstrations in vivo (Abstract; [0023]; [0065]-[0069]; [0077]); Morales teaches 6-OH-CBD-triacetate as prodrugs releasing the hydroxyl active form from CYP3A- and CYP2C- metabolism as having therapeutic potential as an anti-convulsant in vivo (Table 1; Fig. 12; p. 10); and Hampson teaches a genus of CBD analogs encompassing 6-OH-CBD-C4 useful for treating diseases (Example 11, p. 26 compounds 46 and 47; claims 11-13). Thus, the cited prior art provides substantial evidence that one of ordinary skill in the art to consider 6-OH-CBD-C4 as possessing desirable biological activity as an inverse agonist or anti-convulsant with a reasonable expectation of success.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-5, and 24-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 12383512 in view of Li et al. (European Journal of Medicinal Chemistry 192 (2020) 112163, 14 pages), Stott et al. (US20170209390), Morales et al. (Front. Pharmacol. 8:422, 18 pages) and Hampson et al. (US6630507) as applied to the 35 USC 103 rejection above. Although the claims at issue are not identical, they are not patentably distinct from each other because the patent claims treating epilepsy with 6-OH-CBD.
Response to Remarks - Double Patenting
Applicant argues in the same manner as with the 35 USC 103 rejection above. The arguments are not persuasive for the same reasons as above.
Conclusion
No claims allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT H HAVLIN whose telephone number is (571)272-9066. The examiner can normally be reached 9am - 6pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney Klinkel can be reached at (571) 270-5293. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ROBERT H HAVLIN/Primary Patent Examiner, Art Unit 1626
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