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 .
Priority
This application is a Continuation of U.S. App. No. 16/425,744, filed 5/29/2019, which is a Continuation-in-Part of U.S. App. No. 16/110,954, filed 8/23/2018; which is a Continuation-in-Part of International App. No. PCT/US18/41710, filed 7/11/2018; which claims the benefit of and priority to U.S. Provisional App. No. 62/531,123, filed 7/11/2017. International App. No. PCT/US18/41710, filed 7/11/2018 is a Continuation- in-Part of International App. No. PCT/US18/24409, filed 3/26/2018; which claims the benefit of and priority to U.S. Provisional App. Nos. 62/588,662, filed 11/20/2017 and 62/621,166, filed 1/24/2018.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
None of provisional applications 62/531,123, 62/588,662 or 62/621,166 disclose that the glycotransferase is one of the recited proteins herein encoded by the one of the claimed nucleotide sequences. Thus, the earliest priority date for claims 2-4, 9-11, and 14-16 is that of PCT/US18/24409, filed 3/26/2018, which provides adequate support under the requirements of 112(a) for these claimed embodiments, including the claimed sequences.
For the claims not directed to a specific enzyme having a specific sequence, the effective priority date is 11/20/2017, that of 62/588,662 which discloses glycosylated cannabinoids produced with recombinant yeast cells.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 8/2/2023 (three) are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. It is noted that copies of the cited foreign patent documents and NPL references are available in the parent applications 16/110,954 and 16/425,744. One submission is being crossed out because it is not in compliance with 37 CFR 1.98 (a)(1)(ii). Accordingly, the 2 information disclosure statements are being considered by the examiner and the third is placed in the file history but has not been considered.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, or were provided on the considered IDS forms above, they have not been considered.
Due to the large number of references, if there are any particular references that the Applicant deems relevant to patentability, the Applicant is respectfully asked to point out and/or provide a brief description of such references.
Election/Restrictions
Applicant’s election without traverse of the species of the invention wherein the heterologous glycosyltransferase is NtGT4 from tobacco (Nicotiana tabacum), encoded by the nucleotide sequence of SEQ ID NO: 57 in the reply filed on 3/16/2026 is acknowledged.
Upon further consideration, because an exhaustive search of the prior art did not find the claimed elected species of NtGT4 from tobacco with the nucleotide sequence of SEQ ID NO: 57, the search was broadened to include that of SEQ ID NO:7 encoding a glycotransferase, which pertains to the 76G1 UDP-glycotransferase from Stevia rebaudiana, which is encompassed by claims 1, 3-8, 10-13, and 15-16.
Claims 1-16 are pending and were examined on the merits herein.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Because of the length of the specification, the paragraph numbers of the published application, US PGPub No. 20240207179, are referred to herein.
The disclosure is objected to because of the following informalities:
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See the uses of “http” at [0390], and [1116] (e.g. in the references). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
TRADE NAMES, TRADEMARKS, AND OTHER MARKS USED IN COMMERCE:
The use of the terms Q5® DNA polymerase ([0376]); SUPERSCRIPT® III cDNA ([0372];[0388]) ; TRITON™ X-100 and TWEEN® 20 ([0355]; [0373]; [0374]; and [0375]) which are each a trade name or a mark used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks (see MPEP 608.01(v) and 608.01(u)).
Appropriate correction is required.
Claim Objections
Claims 1, 8, 13, and 15 are objected to because of the following informalities:
Claims 1, 8, and 13 each recite the term “promotor”, which should be “promoter” (the accepted spelling for a DNA region where transcription begins).
Claim 15 recites, in line 2, “from the group of consisting of:”, which appears to an error and instead should say “from the group consisting of:”, if that is what Applicant intending.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 2-4, 9-11, 14-16 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.
Claims 2, 3, 9, 10, 14, and 15 each recite the phrase “or a fragment thereof” after a list of potential alternatives from which to choose.
Claims 9, 10, 14, and 15 also recite: “selected from the group consisting of ..., or a fragment thereof” and each recite a list of alternatives to select among.
These claims are indefinite because there is no manner for one to determine the metes and bounds of the claimed subject matter. There is no indication as to what is required to constitute a “fragment thereof”. How much of the enzyme is required? Would only a small peptide having the claimed activity be within the claim scope? Or is there a certain percent identity or percent similarity that is required of the enzyme? Because these list of alternatives are open-ended in regards to the structure of the glycosyltransferase fragment, the claims are rendered indefinite.
Further, for claims 9-10, 14, and 15, the language “selected from the group consisting of” indicates a closed list or a Markush group, and should end in “and” and not “or”. The recitation of both the closed “consisting of” and the open-ended “or a fragment thereof” renders the lists indefinite as one would not be adequate notified of the scope of the claim protection which is sought in the Markush grouping.
Claims 3, 10, and 15 each recite the limitation "said heterologous glycosyltransferase is selected from:" and then provide a listing of sequences, all of which appear to be nucleotide sequences. There is insufficient antecedent basis for this limitation in the claim, because the heterologous glycosyltransferase is a protein (e.g. enzyme) that comprises an amino acid sequence, however the recites sequences are nucleic acid sequences. The independent claims recite a “heterologous nucleotide sequence” which encodes a heterologous glycosyltransferase. The scope of the claim is uncertain because the protein sequence and the nucleotide sequence that encodes it are not exactly interchangeable. In such cases, the nucleotide sequence may have a number of truncations, open reading frames or other non-translated regions. For the sake of correctness, it is recommended to amend the claims to say “the heterologous nucleotide sequence comprises a sequence that is selected from:...” or similar language thereto.
Claims 4, 11, and 16 also recite similar nucleic acid sequences, and recite nucleotide sequences with at least 90% sequence identity to the SEQ ID NO’s. As described above, as the claims are reciting nucleotide sequences, there is insufficient antecedent basis for this limitation because it is unclear whether an amino acid sequence or the nucleotide sequence encoding the heterologous glycosyltransferase is to be compared to set forth the scope of the claim. Correction to the claims to recite “the heterologous nucleotide sequence comprises...” or similar language thereto is recommended.
Claim Rejections - 35 USC § 112(a) - Written Description
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 7 and 12-16 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.
The paragraph numbers of the published application, US PGPub No. 20240207179, are referred to herein.
Claim 7 recites: “said cannabinoid glycoside comprises an acetylated cannabinoid glycoside generated by incubating the cannabinoid with the yeast cell culture.”
Claim 12 recites: “said cannabinoid glycoside comprises an acetylated cannabinoid glycoside generated by incubating the cannabinoid with the yeast cells.”
Claim 13 (and claims 14-16 dependent thereof) recites that “the acetylated cannabinoid glycoside is generated by incubating a quantity of a cannabinoid selected from: CBD, CBDA, THC, THCA or a combination of the same, in a suspension cell culture of genetically modified yeast cells expressing a heterologous nucleotide sequence, operably linked to a promotor, encoding a heterologous glycosyltransferase having activity toward the cannabinoid.”
The claims require one or more acetylated cannabinoid glycosides generated by incubating a cannabinoid with genetically modified yeast cells. There is no further limitation regarding the species or strain of the yeast cells. The the full breadth of the claim scope includes any and all yeasts expressing the described glycotransferases capable of acting on the claimed cannabinoids.
The specification does not provide any evidence of acetylated cannabinoid glycosides produced by yeast cells, nor is there an adequate description of these molecules produced by yeast in the specification or recognized in the art.
MPEP § 2163.03(V). describes an original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement." Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
MPEP § 2163.(II)(A)(3)(a) states that the written description requirement may be satisfied through sufficient description of a representative number of species by actual reduction to practice or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
The specification fails to reasonably describe the claimed invention by providing identifying characteristics, genetic manipulations, or functional properties of yeast cells that are necessary to produce acetylated cannabinoid glycosides.
The instant specification does not disclose any relevant identifying characteristics of the yeast cells necessary to produce the acetylated cannabinoid glycosides, such as structural or other physical properties, or even functional characteristics coupled with a known or disclosed correlation between function and structure, such that the entirety of the claimed genus is encompassed by the description in the disclosure.
There is no description in the disclosure of any yeast cells that produce acetylated cannabinoid glycosides. Additionally, there is no explicit teaching or suggestion in the specification that the yeast are engineered to express an enzyme (such as an acetyltransferase protein) having acetylation activity toward one or more cannabinoids. The use of yeast for producing acetylated cannabinoid glycosides appears to be only prophetic or speculative.
Turning to the relevant art, there is no description of the production of acetylated cannabinoid glycosides in yeast before or around the time of the instant invention.
Alviar et al. (US PGPub No. 20210189444 to Demetrix Inc.) pertains to methods of purifying cannabinoids or cannabinoid derivatives produced using modified host cells and recovering the resulting cannabinoid or cannabinoid derivative preparations and teaches that yeast cells are used as the host cells ([0243], Example 1, [0455]). Alviar describes that additional cannabinoid derivatives of the cannabinoid derivative preparations of the disclosure may include derivatives that have been modified via organic synthesis or an enzymatic route to modify drug metabolism and pharmacokinetics (e.g., solubility, bioavailability, absorption, distribution, half-life and metabolic clearance). “Modification examples may include, but are not limited to, halogenation, acetylation, and methylation” ([0230]). However, there is no discussion of in vivo acetylation as claimed herein, instead this suggests that such modifications are typically done in vitro or through organic synthesis to result in derivatives with the desired properties, as is recognized in the pharmaceutical arts.
Zipp et al. (WO 2017053574, hereafter “Zipp”) discloses producing cannabinoid glycosides (Abstract, Title) and teaches using a UDP-glucosyltransferase from Stevia rebaudiana, expressed in yeast (Pichia pastoris) ([00116]; [00119]). However Zipp does not teach that the cannabinoid glycosides produced in yeast are acetylated, in fact Zipp states that “Alternative strategies to further improve the solubility and delivery of cannabinoids and other compounds described herein include their glycosylation and then functionalizing the sugar moieties with additional ligands or modifications. Examples of this include sulfation, myristoylation, phosphorylation, acetylation, etc.” ([00127]). Thus, Zipp suggests that acetylation can be performed on the cannabinoid glycosides in order to adjust the properties of the compounds, but does not demonstrate or suggest that this is done in yeast.
The disclosure mentions the in vitro use of acetyltransferases, but does not provide for the in vivo expression of such enzymes in yeast. Further, the review article by D'Auria (“Acyltransferases in plants: a good time to be BAHD.” Current opinion in plant biology vol. 9,3 (2006): 331-40. doi:10.1016/j.pbi.2006.03.016) describes that acylation (of which acetylation is a common type) is a common and biochemically significant modification of plant secondary metabolites (Abstract). D'Auria discuses that plant BAHD acyltransferases constitute a large diverse family of acyl CoA-utilizing enzymes and that a vast majority of these enzymes utilize acetyl-CoA as the major acyl donor (see Table 1 and Figure 3, pg. 335, right col, last paragraph). D'Auria teaches that just within a single species, there has been found to exist at least 64 (for A. thaliana) or at least 119 (for Oryza sativa) different BAHD acyltransferases (see pg. 337 section: “BAHD families within a single species”). D’Auria also states that “predicting substrate specificity on the basis of sequence homology has proven to be difficult with BAHD members” (pg. 337, right col, 2nd paragraph). Thus it is evident from the art, that the diversity of plant acetyltransferases is vast, and the instant specification does not provide any guidance as to which acetyltransferases could use the claimed cannabinoid glycosides as a substrate.
Because the production of acetylated cannabinoid glycosides in yeast has not been established in the art, the teachings and working examples of the disclosure must be adequate to ensure that Applicant’s had possession of the full scope of the claimed invention.
Embodiments 4 and 16 in [0047] of the specification describes that water soluble acetylated cannabinoid glycoside comprises a water soluble acetylated cannabinoid glycoside generated in vitro through incubation with a glycosyltransferase protein having glycosylation activity towards one or more cannabinoids and acetyltransferase protein having acetylation activity toward one or more cannabinoids. However this is a description of an embodiment wherein the compounds are produced using in vitro enzymatic treatment, and is not relevant to the claimed subject matter of producing the acetylated cannabinoid glycoside in yeast.
The working examples in the specification that involve a reduction of the invention to practice include expressing vectors and producing cannabinoid glycosides in a plant model, Nicotiana benthamiana ([0342]-[0356]). In Example 9, CBGA (a CBDA precursor) acetylated primary glycoside was detected in all samples, including WT control, providing evidence of endogenous acetylation, however there is no disclosure of acetylated CBD or CBDA ([0351]-[0356], Fig. 21 and Table 7). However, the presented data only demonstrates acetylation of the precursor CBGA in this plant model. Using Agrobacterium infiltration of these plasmid constructs, various strains of Cannabis sativa were transfected and produced accumulation of hydroxylated and/or glycosylated cannabinoids, in this case CBDA (Example 11, [0357]), however no acetylated glycosides are demonstrated therein.
Examples 11, 12, and 15-18 demonstrate an exemplary yeast-cell expression system based on the methylotrophic yeast Pichia pastoris ([0387]-[0395]). These examples also test Tobacco BY2 cells (e.g. see Example 13, [0389]) and contrast the differences in the two cell expression systems. In [0394], Applicant states that “we were able to identify the molecules in the chromatographic analysis and produce extracted ion chromatograms for peak integration as illustrated in FIGS. 38-40 ... Based on these results we identified cannabinoid molecules containing up to two glycosides moieties and an O-acetyl glycoside. Summaries of those identifications are presented in Tables 11 and 12 for exemplary cannabinoids CBGA and CBDA respectively.”. Examination of Figures 38-40 show that the profiles of the cannabinoid glycosides were distinct for the modified Pichia pastoris yeast cells and the modified tobacco BY2 cells. Particularly, Figs 38 and 39 illustrates the results from the Pichia pastoris cell extracts and cell culture supernatant and do not have a peak representing the O-acetyl glycoside, as is distinctly pointed out in Fig. 40 for the tobacco cell extracts.
Thus, the specification provides zero examples of the composition having acetylated cannabinoid glycosides produced in yeast as required of claims 7 and 12-16. The discussions in the specification demonstrate that acetylated cannabinoid glycosides can be produced in plant cells, however, these are not demonstrated in yeast cells as required of the instant claims. There is no convincing evidence that the embodied yeast cells provide the acetylated cannabinoid glycosides required of these claims.
Further, there is no evidence that, at the time of filing, the Applicant possessed any additional representative species of the full genus of compounds as recited in the claims.
Claims 7 and 12-16 are thus rejected under 35 U.S.C. § 112(a) because the claimed subject matter is not described in the specification in such a way as to reasonably convey to a skilled artisan that the inventor, or a joint inventor, had possession of the claimed invention.
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.
Claims 1, 3-5, 8, and 10-11 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Zipp et al. (WO 2017053574, hereafter “Zipp”).
Zipp pertains to cannabinoid glycoside prodrugs and methods of forming the cannabinoid glycoside prodrugs through glycosyltransferase mediated glycosylation of cannabinoid molecules (Abstract, Claim 1). See also: “[0015] Figure 2 illustrates possible products of the glycosylation of cannabidiol (CBD).”, “[0020] Figure 7 illustrates possible products of the glycosylation of tetrahydrocannabinol (Δ9-THC).”, “[0021] Figure 8 illustrates possible products of the glycosylation of cannabinol (CBN).”
Regarding claim 1, Zipp discloses compositions having cannabinoid glycosides in an aqueous solution ([00117]: “Glycosylation of cannabinoids improves solubility in aqueous solutions” ; [0061]: “The increased aqueous solubility of the cannabinoid glycoside prodrugs of the present invention also enables new formulations for delivery in transdermal or aqueous formulations that would not have been achievable if formulating hydrophobic cannabinoid, endocannabinoid and vanilloid molecules”; [00266]: “an aqueous solution of a mixture of CBD-glycosides was administered to a mouse by oral gavage”).
Zipp discloses producing the cannabinoid glycosides using a UDP-glucosyltransferase, UGT76G1 from Stevia rebaudiana, expressed in yeast (Pichia pastoris) ([00116]; [00119]: “It has been found that the UGT76G1 enzyme (SEQ ID NO.1) from Stevia rebaudiana transfers a glucose molecule from the sugar donor UDP-glucose (UDPG) to the hydroxyl groups of CBD to create novel CBD-O-glycosides (Table 1, FIGS. 2 & 4). The UDPG is inverted by UGT76G1 to produce β-D-glucose residues covalently linked through the to the hydroxyl acceptor sites on CBD. To improve the catalytic efficiency UGT76G1 open reading frame (ORF) codon optimization was performed (SEQ ID NOs.: 4 and 6) for expression in Pichia pastoris.”; see also [00139]-[00141]; [00200]; [00212]-[00213] regarding expression of glycosyltransferase)
Because Zipp discloses one or more compositions having an aqueous solution with cannabinoid glycosides, produced using a heterologous glycosyltransferase expressed in yeast, the reference is considered to anticipate the invention of claim 1.
Claims 3 and 4 recite, as best understood according to the B.R.I. in light of the issues identified in the rejection under 112(b) above, that the heterologous glycosyltransferase is one of the proteins encoded by the sequences listed therein. It is noted that the instant SEQ ID NO:7 is derived from the Stevia rebaudiana UGT76G1 sequence and the resulting enzyme that is produced is identical to at least one enzyme disclosed in Zipp (see the comparison of the instant SEQ ID NO: 8 to the amino acid of SEQ ID NO: 7 of Zipp in the appendix below). Further, SEQ ID NO: 1 of Zipp is 99.9% identical to that of the instant SEQ ID NO:8, and the only difference is a conservative substitution of R212 to K.
Because the composition disclosed in Zipp is practically identical, and Zipp discloses using at least one enzyme which is 100% identical to an enzyme which is instantly claimed, the disclosure of Zipp is found to anticipate claims 3 and 4, because at least one of the heterologous glycosyltransferases is anticipated.
Regarding claim 5, Zipp discloses that the aqueous solution for the cannabinoid glycoside composition can be water or saline, e.g. a sodium chloride solution ([0094]: “Acceptable vehicles and solvents that can be employed include, but are not limited to, water, Ringer's solution, lactated Ringer's solution and isotonic sodium chloride solution”).
Regarding claims 8, 10, and 11, claim 8 recites a composition that comprises a dehydrated powder or liquid containing an isolated cannabinoid glycoside. The preamble recites “A consumable food additive”, which amounts to a recitation of an intended use. This does not impart any requirements to the structure of the claimed product. See MPEP § 2111.02 and § 2112.01 regarding properties of Composition, Product, and Apparatus Claims.
Zipp discloses pharmaceutical compositions comprising isolated cannabinoid glycosides that can be in liquid form ([0088]: “Pharmaceutical compositions formulated as aqueous suspensions”) or in powdered form ([0090]: “The pharmaceutical compositions can be formulated as a dispersible powder or granules”). The modified cannabinoids are produced using recombinantly expressed heterologous glycosyltransferases in genetically modified yeast, as explained above.
Zipp discloses that the compositions may be mixed with foods, including syrup, sweetening agents, flavoring agents, and yogurt ([0092]). Regarding the intended use of the preamble of claim 8, it is noted that food additives and pharmaceutical compositions can be identical and interchangeable, as it may be desirable to make a pharmaceutical composition more palatable by mixing it with food. Regardless, the structure of the composition disclosed in Zipp is essentially identical to that which is instantly claimed.
In regards to claims 10 and 11, the limitations are essentially the same as those of claims 3 and 4 above, and thus are rejected as anticipated by Zipp for the same reasons.
Claims 1, 3-5, 8, and 10-11 are thus rejected as being anticipated by Zipp.
Please note, since the Office does not have the facilities for examining and comparing Applicants’ composition with the composition of the prior art, the burden is on applicant to show a novel or unobvious difference between the claimed product and the product of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980), and “as a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith.” In re Brown, 459 F.2d 531, 535, 173 USPQ 685, 688 (CCPA 1972).
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.
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.
Claims 1, 3-6, 8, and 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Zipp et al. (WO 2017053574, “Zipp”).
Zipp teaches one or more compositions having an aqueous solution with cannabinoid glycosides, produced using a heterologous glycosyltransferase expressed in yeast, including using UGT76G1 from Stevia rebaudiana expressed in yeast (Pichia pastoris), and thus, Zipp is considered to anticipate or make obvious all of the limitations of claims 1, 3-5, 8, and 10-11, as described above.
However, Zipp does not explicitly teach that the pH of the aqueous solution is at or below pH 7.4, as required in claim 6.
Zipp does teach that the aqueous solution for the cannabinoid glycoside composition is water or saline, e.g. a sodium chloride solution ([0094]). Water, especially purified or distilled water, is neutral, having a pH 7.0, as would be recognized by one of ordinary skill in the art. Thus, the teaching of Zipp for producing an aqueous solution in water would naturally result in using an aqueous solution with a pH at or below 7.4. Further, a sodium chloride solution would also be neutral, pH 7, absent any carbonic acid formation due to dissolved carbon dioxide, which would result in a pH lower than 7, still within the range of the instant claim 6.
Therefore before the effective filing date of the instant invention, to one of ordinary skill in the art, the limitation of claim 6, that the pH is at or below 7.4 would have been prima facie obvious, because the reference teaches using neutral aqueous solutions, and such optimization of pH is well-known to those in the art.
Because Zipp teaches using neutral water or NaCl solutions, arriving at the instantly claimed pH of 7.4 or less would have naturally followed from the teachings of the reference, with a high expectation of success. Regardless, it is accepted that the determination of a suitable or effective concentration can be determined by one of ordinary skill in the art through the use of routine or manipulative experimentation to obtain optimal results, as pH is a known variable parameter attainable within the art. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Thus, claim 6 is rejected under 35 U.S.C. § 103.
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.
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Claims 1-6 and 8-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 11,466,281. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘281 patent anticipate or make obvious each of the instant claims
Claim 1 of the ‘281 reference patent recites:
1. An in vivo method for the generation of water-soluble cannabinoids in a yeast cell suspension culture comprising the steps:
(a) genetically modified a yeast cell to express a heterologous nucleotide sequence encoding at least one heterologous glycosyltransferase, operably linked to a promotor, wherein said at least one heterologous glycosyltransferase exhibits activity towards one or more cannabinoids and wherein said nucleotide sequence encoding said at least one heterologous glycosyltransferase is selected from the group consisting of: SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 57, and SEQ ID NO. 59;
(b) establishing a suspension cell culture of said genetically modified yeast cells;
(c) introducing said one or more cannabinoids to said suspension cell culture of genetically modified yeast cells; and
(d) isolating one or more glycosylated cannabinoids from said suspension cell culture.
Claim 2 of the reference patent recites that the yeast cells comprise one of genetically modified Pichia pastoris cells, genetically modified Saccharomyces cerevisiae cells, and genetically modified Kluyveromyces marxianus cells. Claim 3 limits the nucleotide sequence encoding the heterologous glycosyltransferase to SEQ ID NO. 57 or SEQ ID NO. 59.
Thus, the subject matter of the ‘281 patent encompasses water soluble glycosylated cannabinoids, including at least the cannabinoid CBDA (as evidenced in FIG. 38 and Col. 36, lines 30-35). MPEP §804.II.B.1. establishes that "The Patent and Trademark Office (‘PTO’) determines the scope of the claims in patent applications not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction ‘in light of the specification as it would be interpreted by one of ordinary skill in the art.’ " Phillips v. AWH Corp., 415 F.3d 1303, 1316, 75 USPQ2d 1321, 1329 (Fed. Cir. 2005) (en banc) (quoting In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364, 70 USPQ2d 1827, 1830 (Fed. Cir. 2004);” and also describes that “the portion of the specification of the reference that describes subject matter that falls within the scope of a reference claim may be relied upon to properly construe the scope of that claim. In particular, when ascertaining the scope of the reference’s claim(s) to a compound, the examiner should consider the reference’s specification, including all of the compound’s uses that are disclosed. See Sun Pharm. Indus., 611 F.3d at 1386-88, 95 USPQ2d at 1801-02.” Further, MPEP §804.II.B.1. also states that “If the reference patent discloses several species within the scope of the reference genus claim, that portion of the disclosure should be analyzed to properly construe the reference patent claim and determine whether it anticipates or renders obvious the claim in the application being examined”.
The instant claimed composition of an aqueous solution (i.e. a water-based solution) having cannabinoid glycosides (i.e. glycosylated cannabinoids) using a genetically modified yeast cells expressing a heterologous glycosyltransferase, as in the instant claim 1, would have thus been prima facie obvious over the method disclosed in the ‘281 patent claims.
Regarding claims 2-4, the reference patent claims recite methods for using yeast cells for producing cannabinoid glycosides that express sequences identical to those of the instantly recited SEQ ID NO. 57 and SEQ ID NO. 59, inter alia. The sequences of the ‘281 patent and the instant application are the same. SEQ ID NO: 57 in both the reference patent and the instant application recite encode the glycosyltransferase NtGT4, while SEQ ID NO: 59 encodes NtGT5.
Regarding claims 5 and 6, the methods recited in the ‘281 patent yield “water-soluble” glycosylated cannabinoids. Therefore, the use of water as the aqueous solution in which they are dissolved would have been prima facie obvious. Further, water is recognized to have a neutral pH of 7.0, and thus this disclosure would also fulfill the limitations of claim 6.
Regarding claims 8-11, claim 8 recites a composition that comprises a dehydrated powder or liquid containing an isolated cannabinoid glycoside. The preamble recites “A consumable food additive”, which amounts to a recitation of an intended use. This does not impart any requirements to the structure of the claimed product. See MPEP § 2111.02 and § 2112.01 regarding properties of Composition, Product, and Apparatus Claims.
The ‘281 patent claims discloses a method for producing a composition that is essentially identical to that which is instantly claimed, except for the recitation of the intended use as a liquid that is added to a food product. Regardless, the instantly claimed composition of an aqueous solution (i.e. a water-based solution) having water-soluble cannabinoid glycosides made using genetically modified yeast cells expressing a heterologous glycosyltransferase, would have been prima facie obvious over the claims of the ‘281 patent. The intended use of the liquid composition for a food additive does not impart any structural requirements that differ from the composition recited in claim 1. The instantly claimed invention is not patentably distinct from an aqueous solution having the water-soluble cannabinoid glycosides of in the ‘281 patent claims.
Regarding claims 9-11, the use of at least one or more of the claimed glycotransferases would have been prima facie obvious, because the sequences disclosed in the ‘281 patent are identical to those of the instant claims. Particularly, it would have been obvious to use a yeast cell system expressing NtGT4 (with SEQ ID NO. 57) or NtGT5 (with SEQ ID NO. 59). The rationale is the same as that explained above for the similar subject matter of claims 2-4.
Therefore, claims 1-6 and 8-11 are rejected on the grounds of nonstatutory double patenting as being rendered obvious by the claimed subject matter of U.S. 11,466,281.
Claims 1, 5-6, and 8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 4-5 of copending Application No. 17/189063 (reference application; USPGPUB US 20220267820-A1). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the 17/189063 application make obvious the instantly recited invention.
Claim 1 of the 17/189063 application recites a method for producing select water-soluble cannabinoid compounds, and includes the step of providing a yeast cell expressing a heterologous nucleotide sequence, operably linked to a promoter encoding a UDP-glycosyltransferase having glycosylation activity towards a cannabinoid selected from cannabidiol (CBD) and THC, and forming a cannabinoid glycoside using the yeast culture.
The instant claimed composition of an aqueous solution (i.e. a water-based solution) having cannabinoid glycosides (i.e. glycosylated cannabinoids) using a genetically modified yeast cells expressing a heterologous glycosyltransferase, as in the instant claim 1, would have thus been prima facie obvious over the method disclosed in the ‘063 application.
Regarding claims 5 and 6, the methods recited in the ‘063 application result in “water-soluble” glycosylated cannabinoids. Therefore, the use of water as the aqueous solution in which they are dissolved would have been prima facie obvious. Further, water is recognized to have a neutral pH of 7.0, and thus this disclosure would also fulfill the limitations of claim 6.
Claim 8 recites a composition that comprises a dehydrated powder or liquid containing an isolated cannabinoid glycoside. The preamble recites “A consumable food additive”, which amounts to a recitation of an intended use. This does not impart any requirements to the structure of the claimed product. See MPEP § 2111.02 and § 2112.01 regarding properties of Composition, Product, and Apparatus Claims.
The ‘063 application claims a method for producing a composition that is essentially identical to that which is instantly claimed, except for the recitation of the intended use as a liquid that is added to a food product. Regardless, the instantly claimed composition of an aqueous solution having water-soluble cannabinoid glycosides made using genetically modified yeast cells expressing a heterologous glycosyltransferase, would have been prima facie obvious over the claims of the reference application. The intended use of the liquid composition for a food additive does not impart any structural requirements. Claim 8 is therefore not patentably distinct from an aqueous solution having the water-soluble cannabinoid glycosides of in the ‘281 patent claims, which would have been prima facie obvious for all of the reasons discussed above.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3-6, 8, and 10-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 4-5 of copending Application No. 17/189063 in view of Zipp et al. (WO 2017053574, hereafter “Zipp”).
As discussed above, the instantly claimed composition of an aqueous solution (i.e. a water-based solution which includes liquid food additives) having cannabinoid glycosides (i.e. glycosylated cannabinoids) using a genetically modified yeast cells expressing a heterologous glycosyltransferase, as in the instant claim 1, would have thus been prima facie obvious over the method disclosed in the ‘063 application. Further, the limitations of claims 5-6 and 8 were also found to be obvious over the claims of the ‘063 application, for the reasons discussed above.
However, the claims of the ‘063 application do not recite that the heterologous glycosyltransferase is an enzymes encoded by the sequences listed in claims 3, 4, 10, or 11.
The relevant teachings of Zipp include all of those discussed previously.
Zipp pertains to cannabinoid glycoside prodrugs and methods of forming the cannabinoid glycoside prodrugs through glycosyltransferase mediated glycosylation of cannabinoid molecules (Abstract, Claim 1). Zipp teaches compositions having an aqueous solution with cannabinoid glycosides, including cannabidiol (CBD) glycosides, produced using a heterologous glycosyltransferase expressed in yeast as recited in the instant claims.
Zipp teaches producing cannabinoid glycosides using a UDP-glucosyltransferase, UGT76G1 from Stevia rebaudiana, expressed in yeast (Pichia pastoris) ([00116]; [00119]) The instant SEQ ID NO:7 is also derived from the Stevia rebaudiana UGT76G1 sequence and the resulting enzyme that is produced is identical to at least one enzyme disclosed in Zipp (see the comparison of the instant SEQ ID NO: 8 to the amino acid of SEQ ID NO: 7 of Zipp in the appendix below).
In view of the teaching in Zipp, it would have been obvious to modify the method of the ‘063 application claims by substituting the UDP-glucosyltransferase UGT76G1 taught in Zipp, which is 100% identical to at least one enzyme which is instantly claimed (e.g. the enzyme of SEQ ID NO: 8 encoded by SEQ ID NO: 7), for the UDP-glucosyltransferase recited in the reference claims, because Zipp also pertains to producing cannabidiol (CBD) glycosides and Zipp teaches that UGT76G1 can be used successfully for such a process.
The substitution and selection of enzymes that are known in the art for the same purpose would have been merely a matter of judicial selection to one having ordinary skill in the art. The produced water-soluble cannabinoid glycosides would have predictably been the same as those encompasses in the instant claims. Because the UGT76G1 was taught in Zipp to produce CBD glycosides, it is obvious to use it in the method of the reference claims with a reasonable expectation of success.
Therefore, the additional limitations of claims 3-4 and 10-11 would have been obvious over the ‘063 application claims, in view of Zipp.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1-16 are rejected.
No claims are allowable.
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/A.T.M./Examiner, Art Unit 1655
/ANAND U DESAI/Supervisory Patent Examiner, Art Unit 1655
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APPENDIX A: Sequence Alignment of Instant SEQ ID NO:8 to SEQ ID NO:7 of Zipp.
Prosecution Insights