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 .
Status of the Claims
Claims 1-25 are pending in the instant application.
Priority
This application claims priority to U.S. Provisional Application 63/170,449, filed 04/03/2021.
Claim Objections
Claims 1, 4, 19 and 25 are objected to because they use inconsistent terminology. Claims 1 and 19 recite the term pancreatic cancer, whereas claims 4 and 25 recite the abbreviation PC. Furthermore, the abbreviation PC is not defined in the claims. In a review of the specification, it is noted that the specification teaches PC is pancreatic cancer. To overcome the objection, Applicant should include the abbreviation with the first iteration of the term for consistency.
Claims 1-2, 5-7, 9-10, 13-14, 17-20, and 23-25 are objected to because they use inconsistent terminology. Claims 1-2, 5-7, 9-10, 19, and 25 recite the term cannabidiol, while claims 13-14, 17-18, 20, and 23-24 recite the abbreviation CBD. Furthermore, the abbreviation CBD is not defined in the claims. In a review of the specification, it is noted that the specification teaches CBD is cannabidiol. To overcome the objection, Applicant should include the abbreviation with the first iteration of the term for consistency.
Claims 1-2, 5-6, 8-9, 11, 13, 15, 17, 19, 21, and 23-25 are objected to because they use inconsistent terminology. Claims 1-2, 5-6, 8-9, 11, 19, and 25 recite the term “melatonin”, while claims 13, 15, 17, 21, and 23-24 recite the abbreviation MLT. Furthermore, the abbreviation MLT is not defined in the claims. In a review of the specification, it is noted that the specification teaches MLT is melatonin. To overcome the objection, Applicant should include the abbreviation with the first iteration of the term for consistency.
Claims 1-2, 5-6, 12-13, 16-17, and 22-25 are objected to because they recite the abbreviation AKBA, but this abbreviation is not spelled out in the claims. In a review of the specification, it is noted that the specification teaches AKBA is acetyl-11-keto-β-boswellic acid. To overcome the objection, Applicant should include the full term with the first iteration of the abbreviation in the claims.
Claim 6 recites the phrase “wherein the at least one compound cannabidiol…” This phrase is grammatically incorrect. Applicant should add the term “is” or another verb phrase such as “consists of” between the terms “compound” and “cannabidiol”, depending on what scope is meant by the claim. For examination purposes, claim 6 will be interpreted as reading “wherein the at least one compound is cannabidiol…”.
Claim 7 is missing a period at the end. Claims must end with a period; see MPEP 608.01(m).
Claim 20 recites the phrase “wherein amount of CBD”, which should read “wherein the amount of CBD”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
112(a)
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.
Claim 4 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating pancreatic cancer comprising administering a combination of cannabidiol, melatonin, and AKBA, does not reasonably provide enablement for a method of treating pancreatic cancer with any compound. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. See In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
1. The nature of the invention, state and predictability of the art, and relative skill of those in the art
The invention relates to a method of treating a pancreatic cancer in a subject comprising administering an effective amount of at least one compound.
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicant’s invention would generally be a physician with a M.D. degree and several years of experience.
The factor is outweighed, however, by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); Ex parte Sudilovsky 21 USPQ2d 1702 (Applicant’s invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain). As illustrative of the state of the art of treating any cancer, the examiner cites Gura et al. ("Systems for Identifying New Drugs are Often Faulty"); Johnson et al. ("Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials"); and Kunnumakkara et al. (“Cancer drug development: The missing links”).
Gura, cited for evidentiary purposes, teaches that researchers face the problem of sifting through potential anticancer agents to find ones promising enough to make human clinical trials worthwhile and further teach that since formal screening began in 1955, many thousands of drugs have shown activity in either cell or animal models, but only 39 have actually been shown useful for chemotherapy (see page 1041, first and second paragraph). Also, with regard to unpredictability, Johnson, also cited for evidentiary purposes, teaches that the in vivo activity of 39 different agents in a particular histology in a tumor model did not correlate to activity in the same human cancer (see Results on page 1426). In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. Further, the mode of action of anticancer agents is often unknown or very unpredictable and administration of such agents is often accompanied by undesirable side effects.
Furthermore, with regard to unpredictability, Kunnumakkara, cited for evidentiary purposes, teaches there exists a missing connection between preclinical data and clinical findings; although, a significantly huge amount of money is spent in the pre-clinical settings for target validation and drug optimization, most of the therapies fail in the clinical trials till date; this can be due to the reason that the models used in the pre-clinical setting are not the adequate ones to effectively mimic human responses (page 664, right, 2nd paragraph); although highly convenient, cancer cell line models are associated with several limitations as well; for example, existence of genomic instability which may result in differences between the original tumor and the respective cell line, culture conditions that can alter the morphology, gene expression pattern, genomic profile, cellular pathways and culture environment from that of the original tumor, loss of natural tumor heterogeneity; the generic transformations that occur upon culturing of the cancer cells are not restored when regrown in vivo; and cancer cells in the in vitro condition grow in absence of stroma which include lymphatic vessels and blood, associated fibroblasts and immune cells, and lack a complex extracellular matrix; therefore, in vitro data often exhibits fundamental mismatch with those obtained from clinical findings and hence this can be regarded as one prime reason behind the failure of novel drug development (page 665, last bridge paragraph). Kunnumakkara teaches the foremost shortcomings of the use of animal models are their inability to recapitulate the link between the tumor and its microenvironment completely and the requisite of an immunocompromised host; basically, these animal models do not have the ability to reflect all the features of human cancer impeccably. Kunnumakkara teaches that despite the advances in understanding of cancer biology and deriving different novel therapeutic targets, the translation of these understandings into therapies is poor due to higher failure rate (90%). The high failure rate could be due to non-consideration of factors such as clinical translation, drug delivery, drug pharmacokinetics, pre-clinical models, and tumor physiology, which are critical factors.
These articles plainly demonstrate that the art of developing and testing drugs to treat cancer, including pancreatic cancer, particularly for use in humans, is extremely unpredictable.
2. The breadth of the claims
Claim 4 is extremely broad in that it recites the treatment of pancreatic cancer with an effective amount of any compound with no limitations as to structure or even function.
3. The amount of direction or guidance provided and the presence or absence of working examples
The specification provides support for the use of cannabidiol, melatonin, and AKBA to treat pancreatic cancer. Table 5 gives cell line viabilities for different combinations and dosages of cannabidiol, melatonin, and AKBA. Figure 1C supports treatment of pancreatic cancer in vivo for combinations of cannabidiol and melatonin along with gemcitabine, where tumor mass was reduced following such treatment. However, the specification does not provide support for the use of any other compounds, including those with no structural similarity to cannabidiol, melatonin, or AKBA.
4. The quantity of experimentation necessary
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that the data provided for cannabidiol, melatonin, and AKBA would enable one to use any compound to treat pancreatic cancer without undue experimentation. Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and 'patent protection' is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" (42 USPQ 2d 1001, Fed. Circuit 1997).
As noted above, the specification provides no experimental support for the treatment of pancreatic cancer with compounds other than cannabidiol, melatonin, AKBA, or combinations thereof. Determining if any particular compound would treat a pancreatic cancer would require synthesis of the compound, formulation into a suitable dosage form, and subjecting it to clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment. This is undue experimentation given the limited guidance and direction provided by Applicants. As noted supra, even in vitro and in vivo assays do not always correlate to efficacy in humans and are not generally predictive of clinical efficacy.
Accordingly, claim 4 does not comply with the enablement requirement of 35 U.S.C. 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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 1-25 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the term “the subject.” There is insufficient antecedent basis for this limitation in the claim. Because claims 2, 3, 13-18, and 24-25 depend on claim 1, they inherit the lack of antecedent basis and are also rejected.
Claim 13 is 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 13 recites the limitation “wherein the amount of CBD, MLT, and AKBA administered is up to 1 mg”. It is not clear whether each compound is administered up to 1 mg or if the total amount of CBD, MLT, and AKBA is up to 1 mg.
Claims 23 and 24 are rendered vague and indefinite by the phrase “a synergistic effect” because it is unclear as to what amount (e.g., amount range, proportion, and/or ratio) of each claimed ingredient actually define a synergistic amount with respect to the other ingredients so as to produce a synergistic effect. Accordingly, the metes and bounds of this phrase (e.g., the synergistically effective amounts of each ingredient with respect to the others) are not clearly nor adequately delineated with respect to the synergistic amounts of the individual components. Please note that synergism is an unpredictable phenomenon which is highly dependent upon specific proportions and/or amounts of particular ingredients. Accordingly, the recitations of the amounts, ranges, and/or proportions (e.g., ratios) of each claimed ingredient necessary to provide a synergistic combination is deemed essential (see, e.g., MPEP 2172.01) and, thus, should be defined in the independent claim language itself.
Claim 1 recites the limitation “a method of treating a pancreatic cancer”. In a review of the specification, the term "a pancreatic cancer" is not defined; thus, the term is interpreted as pancreatic cancer for examination purposes. However, it is not clear what type or types of pancreatic cancer are claimed and what Applicant means by "a pancreatic cancer". Claims 2-3, 13-17, and 24-25, which depend on claim 1, are rejected for failing to specify what pancreatic cancer is specified.
Claim 4 recites the limitation “a method of treating a PC [pancreatic cancer]”. In a review of the specification, the term "a pancreatic cancer" is not defined; thus, the term is interpreted as pancreatic cancer for examination purposes. However, it is not clear what type or types of pancreatic cancer are claimed and what Applicant means by "a pancreatic cancer". Claims 5-12, which depend on claim 4, are rejected for failing to specify what pancreatic cancer is specified.
Claim 19 recites the limitation “a composition for treating a pancreatic cancer”. In a review of the specification, the term "a pancreatic cancer" is not defined; thus, the term is interpreted as pancreatic cancer for examination purposes. However, it is not clear what type or types of pancreatic cancer are claimed and what Applicant means by "a pancreatic cancer". Claims 20-23, which depend on claim 19, are rejected for failing to specify what pancreatic cancer is specified.
112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 10-12 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 10 depends on claim 9, which recites that the at least one compound is a combination of cannabidiol and melatonin. Claim 10 merely recites that the combination comprises cannabidiol; in other words, this combination may include compounds other than cannabidiol and melatonin. Moreover, the combination of claim 9 already encompasses cannabidiol. Thus, claim 10 fails to further limit the subject matter of claim 9.
Claim 11 recites the combination in claim 10, further consisting of melatonin. Claim 10 depends from claim 9, which is directed to a combination of cannabidiol and melatonin. Thus, the combination already contains melatonin. Thus, claim 11 fails to further limit the subject matter of the claim from which it depends.
Claim 12 recites the combination in claim 11, further consisting of AKBA. Claim 11 recites the combination in claim 10, which depends from claim 9, which is directed to a combination of cannabidiol and melatonin. Claim 11 discloses the combination consists of melatonin. Thus, claim 11 contains closed language and does not allow for any additional components. Thus, claim 12 fail to further limit the subject matter of the claims from which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 19-22 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Claims 19-22 are directed to a combination of cannabidiol, melatonin, and AKBA. Based upon an analysis with respect to the claims as a whole, claims 19-22 are directed to a judicial exception (i.e., law of nature, a natural phenomenon, or an abstract idea) without significantly more. Claims 19-22 recite naturally occurring compounds and as such are directed towards a law of nature and a natural phenomenon. The claimed compounds do not have markedly different characteristics from what occurs in nature, and are a “product of nature” exception. Further, the claims do not include any additional elements that are sufficient to amount to significantly more than the judicial exceptions.
The rationale for this determination is explained below (see also MPEP 2106):
Step 1: Is the claim to a process, machine, manufacture or composition of matter?
The subject matter, within the scope of the instant claims is construed as a composition comprising cannabidiol, melatonin, and AKBA.
Thus, the answer to Step 1 is: Yes, the claims are drawn to a composition of matter.
Step 2A: Is the claim directed to a law of nature, a natural phenomenon, or an abstract idea?
The claimed subject matter appears to describe the mixture of three natural products: cannabidiol, melatonin, and AKBA.
Because each compound is naturally occurring, their combination together in a composition is considered a “product of nature,” which falls within each of the categories: “laws of nature” and “natural phenomena.” Thus, the claims are drawn to judicially recognized exception. See p74623, left column, of the Federal Registry notice: “…Courts have held that naturally occurring products and some man-made products that are essentially no different from a naturally occurring product are ‘‘products of nature’’ that fall under the laws of nature or natural phenomena exception.” (Section I (3); pp. 74622-4, of the Federal Registry notice discusses Natural Products.).
The next question within step 2A is: does the nature-based product show “markedly different characteristics” from any naturally occurring counterpart(s) in their natural state, based on structure, function and/or properties?
As noted by Yang et al. ("Cannabinoids Inhibited Pancreatic Cancer via P-21 Activated Kinase 1 Mediated Pathway", cited in the IDS dated 10/03/2023), cannabidiol is obtained from plant extracts (pg. 2, para. 2). As noted by Xu et al. (“Melatonin is involved in the apoptosis and necrosis of pancreatic cancer cell line SW-1990 via modulating of Bcl-2/Bax balance”), melatonin is produced by the pineal gland of the human body (pg. 133, col. 1). As noted by Park et al. (“Acetyl-11-keto-β-boswellic acid suppresses invasion of pancreatic cancer cells through the downregulation of CXCR4 chemokine receptor expression”), AKBA is found in the plant Boswellia serrata (abstract).
“The markedly different characteristics analysis compares the nature-based product limitation to its naturally occurring counterpart in its natural state. When there is no naturally occurring counterpart to the nature-based product, the comparison should be made to the closest naturally occurring counterpart. In the case of a nature-based combination, the closest counterpart may be the individual nature-based components that form the combination, i.e., the characteristics of the claimed nature-based combination are compared to the characteristics of the components in their natural state”. Thus, Applicant’s claimed composition is essentially directed to a mere aggregation of compounds that each occur naturally.
Establishment of a marked difference cannot be based on some inherent or innate characteristic of the naturally occurring counterpart. See p. 74623, footnote 28: “To show a marked difference, a characteristic must be changed as compared to nature, and cannot be an inherent or innate characteristic of the naturally occurring counterpart. Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130 (1948) (‘‘[The inventor did] not create a state of inhibition or of non-inhibition in the bacteria. Their qualities are the work of nature. Those qualities are of course not patentable.’’); In re Marden, 47 F.2d 958 (CCPA 1931) (eligibility of a claim to ductile vanadium held ineligible, because the ‘‘ductility or malleability of vanadium is . . . one of its inherent characteristics and not a characteristic given to it by virtue of a new combination with other materials or which characteristic is brought about by some chemical reaction or agency which changes its inherent characteristics’’). Further, a difference in a characteristic that came about or was produced independently of any effort or influence by applicant cannot show a marked difference. Roslin, 750 F.3d at 1338 (Because ‘‘any phenotypic differences came about or were produced ‘quite independently of any effort of the patentee’ ’’ and were ‘‘uninfluenced by Roslin’s efforts’’, they ‘‘do not confer eligibility on their claimed subject matter’’ (quoting Funk Bros.)).
In the instant case, there seems to be no indication in the specification that the combination of all of the above natural products has any characteristics (structural, functional or other properties) that are different from the naturally occurring counterpart in its natural state. Thus, the composition does not have markedly different characteristics from what occurs in nature, and is a “product of nature exception”.
Thus, the answer to Step 2A is: Yes, the claims are drawn to a natural composition.
Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exemption?
The claims have no additional elements other than amounts of each compound to be administered. Because the claims do not include any additional features that could add “significantly more” to the exception the answer to Step B is: No, the claims do not recite additional elements that amount significantly more than the judicial exception.
In sum, applicant’s claims 19-22 are not directed to a composition that is markedly different in structure from a naturally-occurring product. Therefore, the claims are not directed to patent-eligible subject matter.
The claims do not qualify as eligible subject matter, and are properly rejected under 35 U.S.C. § 101.
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 4-7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ferro et al. ("GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine”).
Regarding claim 4, Ferro et al. teaches a method of treating a pancreatic cancer in a subject, comprising administering an effective amount of at least one compound (abstract, “KPC mice treated with a combination of the GPR55 antagonist Cannabidiol (CBD) and gemcitabine (GEM, one of the most used drugs to treat PDAC), survived nearly three times longer compared to mice treated with vehicle or GEM alone”).
Regarding claim 5, Ferro et al. teaches a method of treating a pancreatic cancer comprising administering an effective amount of at least one compound, wherein the at least one compound comprises cannabidiol, melatonin, AKBA, or combinations thereof.
Regarding claim 6, Ferro et al. teaches a method of treating a pancreatic cancer comprising administering an effective amount of at least one compound, wherein the at least one compound is cannabidiol, melatonin, AKBA, or combinations thereof (pg. 6374, col. 2, “Lifespan of mice given CBD (mean 25.4 days, median 22 days) was very similar to survival of mice given GEM (mean 27.8 days, median 23.5 days). Survival of mice given the vehicle was: mean 18.6 days, median 20 days.”; survival of mice given CBD is longer than that of mice given the vehicle)
Regarding claim 7, Ferro et al. teaches a method of treating a pancreatic cancer comprising administering an effective amount of at least one compound, wherein the at least one compound is cannabidiol.
Thus, the prior art anticipates the instantly claimed invention.
Claims 4-6 and 8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Xu et al. (“Melatonin is involved in the apoptosis and necrosis of pancreatic cancer cell line SW-1990 via modulating of Bcl-2/Bax balance”).
Regarding claim 4, Xu et al. teaches a method of treating a pancreatic cancer in a subject, comprising administering an effective amount of at least one compound (p. 138, col. 1, “According to the results of the in vivo experiment, the treatment of gemcitabine alone exerted a beneficial effect to the pancreatic cancer in terms of the decreased tumor volume and weight, and the treatment of melatonin alone exerted a similar beneficial effect”).
Regarding claim 5, Xu et al. teaches a method of treating a pancreatic cancer comprising administering an effective amount of at least one compound, wherein the at least one compound comprises cannabidiol, melatonin, AKBA, or combinations thereof.
Regarding claim 6, Xu et al. teaches a method of treating a pancreatic cancer comprising administering an effective amount of at least one compound, wherein the at least one compound is cannabidiol, melatonin, AKBA, or combinations thereof.
Regarding claim 8, Xu et al. teaches a method of treating a pancreatic cancer comprising administering an effective amount of at least one compound, wherein the at least one compound is melatonin.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-12 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Ferro et al. in view of Xu et al. and Park et al (“Acetyl-11-keto-ß-boswellic acid suppresses invasion of pancreatic cancer cells through the downregulation of CXCR4 chemokine receptor expression”).
Regarding claims 4-7, Ferro et al. teaches a method of treating a pancreatic cancer in a subject, comprising administering an effective amount of cannabidiol (abstract, “CBD and THC inhibited the proliferation of PC, PS, and PSC-stimulated PC cells. They also suppressed pancreatic tumour growth in mice”). The rejections for claims 4-7 regarding Ferro et al. are discussed earlier in this Office action (section “Claim Rejections: 35 USC § 102) and are not reiterated here.
Ferro et al. also teaches a combination therapy of CBD with gemcitabine (pg. 2, para. 2, “…CBD inhibited PC growth synergistically with gemcitabine through antagonizing the G protein-coupled receptor GPR55”). Ferro et al. does not teach the use of melatonin or AKBA.
Regarding claims 4-6 and 8, Xu et al. teaches a method of treating a pancreatic cancer in a subject, comprising administering an effective amount of melatonin (pg. 138, para. 1, “According to the results of the in vivo experiment, the treatment of gemcitabine alone exerted a beneficial effect to the pancreatic cancer in terms of the decreased tumor volume and weight, and the treatment of melatonin alone exerted a similar beneficial effect. Furthermore, the tumor volume and weight were decreased more significantly after the combined treatment with melatonin and gemcitabine”). The rejections for claims 4-6 and 8 regarding Xu et al. are discussed earlier in this Office action (section “Claim Rejections: 35 USC § 102) and are not reiterated here.
Xu et al. also teaches a combination therapy of administering melatonin with gemcitabine (ibid.). Xu et al. does not teach the use of CBD or AKBA.
Park et al. teaches a method of treating a pancreatic cancer in a subject, comprising administering an effective amount of AKBA (pg. 29, para. 3 “The result of immunohistochemical analysis showed that AKBA suppressed the expression of CXCR4 in human pancreatic tumor tissues. Western blotting data further confirmed that AKBA decreased the expression of CXCR4 in pancreatic tumor tissues from mice (Fig. 6b). Under these conditions, AKBA reduced tumor growth by 50% and suppressed metastasis to spleen, liver and lung significantly”). Park et al. does not teach the use of cannabidiol or melatonin.
The courts have recognized that combining equivalents known for the same purpose supports a prima facie case of obviousness. See MPEP 2144.06: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See also In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
Because cannabidiol, melatonin, and AKBA are individually known to treat pancreatic cancer, it would have been obvious to one of ordinary skill in the art prior to the filing of the instant application to administer them in combination to treat pancreatic cancer in a subject. One would have had a reasonable expectation of success in doing so based on the teaching of Ferro et al. in view of Xu et al. and Park et al. because each agent works independently to treat pancreatic cancer and thus there is an expectation that the combination would work as well.
Thus, claim 1, which recites a method of treating pancreatic cancer in a subject, comprising administering a combination of cannabidiol, melatonin, and AKBA, is rejected. Similarly, claim 9, directed to using a combination of cannabidiol and melatonin; claim 10, directed to using a combination comprising cannabidiol; claim 11, directed to using a combination comprising cannabidiol and melatonin; and claim 12, directed to using a combination comprising cannabidiol, melatonin, and AKBA, are all rejected.
In addition, as taught by Ferro et al. and Xu et al., cannabidiol and melatonin individually enhance the effect of gemcitabine, so it would have been obvious to administer a combination of cannabidiol, melatonin, and AKBA in combination with another anticancer treatment (in particular, treatment with gemcitabine). Given that CBD and melatonin both individually enhance the effect of gemcitabine, one would have had a reasonable expectation of success that the combination along with AKBA would as well. Thus, claim 2 is rejected.
Furthermore, although these references do not teach the use of cannabidiol, melatonin, or AKBA to treat pancreatic cancer in a human, they treat pancreatic cancer in an animal model. It would have been obvious to one of ordinary skill in the art to try administering a combination of cannabidiol, melatonin, and AKBA to treat pancreatic cancer in a human based on the teachings of Ferro et al. in view of Xu et al. and Park et al. One would have had a reasonable expectation of success in doing so based on the results in animal models. Thus, claim 3 is rejected.
Regarding claim 25, the wherein limitation of this claim is considered to simply express the intended result of a process step positively recited, which is not given patentable weight (See MPEP 2111.04: [T]he court noted (quoting Minton v. Nat'lAss'n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQgd 1614, 1690 (Fed. Cir. 2003)) that a "'whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.'" Hoffer v. Microsoft Corp., 405 F.3d 1396, 1399, 74 USPQgd 1481, 1483 (Fed. Cir. 2005).). In the instant case, the wherein clause is directed to the intended result (i.e. producing percent viability of less than 10%, thereby effectively killing PC cells) of the process step positively recited (i.e. administering cannabidiol, melatonin, and AKBA to a subject suffering from pancreatic cancer). Thus, claim 25 is rejected.
Claims 1 and 4-18 are rejected under 35 U.S.C. 103 as being obvious over Ferro et al. in view of Yang et al. ("Cannabinoids Inhibited Pancreatic Cancer via P-21 Activated Kinase 1 Mediated Pathway", cited in the IDS dated 10/03/2023), Xu et al. and Wang et al. (WO 2017076332 A1; English translation obtained using WIPO PatentScope Translate tool).
As previously discussed, Ferro et al. teaches a method of treating pancreatic cancer in a subject, comprising administering cannabidiol. Ferro et al. further teaches a dosage of 100 mg/kg per mouse (pg. 6374, col. 2, “KPC mice were given CBD (100 mg/kg)…”). Ferro et al. also teaches daily administration of CBD (pg. 6381, “Vehicle and CBD were administered by daily peritoneal injection”). Ferro et al. does not teach the masses of the mice and thus does not teach an amount of CBD administered in the range of 1 µg to 1 mg, nor does it teach that CBD is administered for 72 hours. Ferro et al. also does not teach the use of melatonin or AKBA.
Yang et al. teaches a method of treating pancreatic cancer comprising administering CBD, wherein the concentration of CBD administered ranges from 5-10 µM (pg. 2, para. 4, “…CBD showed a more potent inhibitory effect on these human PC cell lines and achieved reduction of proliferation to less than 40% of the control at 5 µM”; see also Figure 1C, CBD inhibited proliferation in the range of 5-10 µM). Yang et al. does not teach a concentration directly anticipating the claimed range of 1.9-15.2 mg/mL (corresponding to 6.25-100 µM as per line 395 of the instant specification), nor does it teach this dosage in a subject. Yang et al. also does not teach the use of cannabidiol or AKBA.
As previously discussed, Xu et al. teaches a method of treating pancreatic cancer in a subject, comprising administering melatonin. Xu et al. further teaches a method of treating pancreatic cancer in a subject, wherein the amount of melatonin administered is in the range of 1 µg to 1 mg (pg. 135, para. 1, melatonin dosage is 20 mg/kg; pg. 134, col. 2, para. 1, mice weigh 15–16 g; 20 mg/kg*0.015–0.016 kg = 0.30–0.32 mg MLT). Xu et al. also teaches daily administration (pg. 135, para. 1, “melatonin…was administered peritoneally every day until the end of the study”). Xu et al. does not teach that melatonin is administered for 72 hours, nor does it teach the use of cannabidiol or AKBA.
Wang et al. teaches a method of treating pancreatic cancer in a subject, comprising administering AKBA (claim 6; when R is AcO, the compound is AKBA). Wang et al. also teaches a dosage of 0.05 to 500 mg/kg, noting that “this dosage regimen can be adjusted to provide an optimal treatment response” (para. 0083; AKBA is a compound of formula (I)). Wang further teaches that AKBA is administered daily (para. 0083). Wang does not teach that AKBA is administered for 72 hours, nor does it teach the use of cannabidiol or melatonin.
As previously discussed, combining equivalents known for the same purpose supports a prima facie case of obviousness. Because cannabidiol, melatonin, and AKBA are individually known to treat pancreatic cancer, it would have been obvious to one of ordinary skill in the art prior to the filing of the instant application to administer them in combination to treat pancreatic cancer in a subject. One would have had a reasonable expectation of success in doing so based on the teaching of Ferro et al. in view of Xu et al. and Wang et al. because each agent works independently to treat pancreatic cancer and thus there is an expectation that the combination would work as well. Thus, claims 1 and 4-12 are rejected.
Furthermore, regarding claims 13-18, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here 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). See also MPEP 2144.05.
Thus, it would have been prima facie obvious to one of ordinary skill in the art to utilize the amount of cannabidiol and the treatment regimen taught by Ferro et al. as a starting point for optimizing the amount and treatment regimen of cannabidiol used to treat pancreatic cancer because dosage and treatment regimen are result-effective variables, i.e. a variable that achieves a recognized result. Similarly, one could use the amount of melatonin and treatment regimen taught by Xu et al. and the amount of AKBA and treatment regimen taught by Wang et al. as starting points. Therefore, the determination of the optimum or workable dosages in a method comprising administering a combination of CBD, melatonin, and AKBA would have been well within the practice of routine experimentation by the skilled artisan using the teaching of Ferro et al. in view of Xu et al. and Wang et al. Furthermore, absent any evidence demonstrating a patentable difference between the methods in the prior art and the criticality of the claimed dosage range, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan.
Thus, claim 13, directed to the total amount of CBD, melatonin, and AKBA administered, is rejected over Ferro et al. in view of Xu et al. and Wang et al. Claim 14, directed to the amount of CBD administered, is rejected in view of the dosage taught by Ferro et al. Claim 15, directed to the amount of melatonin administered, is rejected in view of the dosage taught by Xu et al. Claim 16, directed to the amount of AKBA administered, is rejected in view of the dosage taught by Wang et al. Claim 17, directed to the treatment regimen for administering the combination, is rejected in view of the daily administration of CBD, melatonin, and AKBA taught by Ferro et al., Xu et al., and Wang et al., respectively. Claim 18, directed to another dosage of CBD, is rejected in view of the dosage taught by Yang et al.
Claims 1 and 19-22 are rejected under 35 U.S.C. 103 as being obvious over Fliri et al. (WO 2020/081513, cited in the IDS dated 10/03/2023) in view of Ferro et al., Xu et al., Wang et al., and Jiang et al.
Regarding claim 1, Fliri et al. teaches a method of treating pancreatic cancer, comprising administering a combination of cannabidiol, melatonin, and AKBA to the subject in need thereof (claim 76, “A method of treating a disease or the symptoms thereof in a mammal, the disease selected from …gall bladder cancer, pancreatic cancer, esophageal cancer,… the method comprising administering…”). Although cannabidiol, melatonin, and AKBA are all listed in the third group, the claim teaches that “at least one of” these compounds is administered and thus may include a combination of all three.
Regarding claim 19, Fliri et al. teaches a composition for treating a pancreatic cancer, comprising cannabidiol, melatonin, and AKBA (claim 1). Similar to claim 76, claim 1 of Fliri et al. recites three groups of compounds, with cannabidiol, melatonin, and AKBA belonging to the third group. The composition includes at least one compound from the third group, and thus may include a combination of all three.
While the reference may not be anticipatory insofar as one must select cannabidiol, melatonin, and AKBA from group 3 as taught by Fliri, as well as pancreatic cancer as the disease to be treated, it remains that it would have been obvious to a person of ordinary skill in the art, to have selected these three compounds along with one compound from group 1 and one compound from group 2 in order to arrive at a method or composition useful for treating pancreatic cancer. The skilled person would have been motivated to do so by the unambiguous disclosure of each compound individually or in combination, along with compounds from groups 1 and 2, to treat pancreatic cancer. This conclusion is supported by the fact that it has long been held in patent prosecution that a reference should be considered as expansively as is reasonably possible in determining the full scope of the contents. Thus, claims 1 and 19 are rejected.
Fliri et al. does not teach dosages for cannabidiol, melatonin, or AKBA.
Regarding claim 20, Ferro et al. teaches a dosage of 100 mg CBD/kg per mouse to treat pancreatic cancer (pg. 6374, col. 2, “KPC mice were given CBD (100 mg/kg)…”). Ferro et al. also teaches administration of CBD by peritoneal injection (pg. 6381, “Vehicle and CBD were administered by daily peritoneal injection”).
Regarding claim 21, Xu et al. teaches a dosage of melatonin in the range of 1 µg to 1 mg to treat pancreatic cancer (pg. 135, para. 1, melatonin dosage is 20 mg/kg; pg. 134, col. 2, para. 1, mice weigh 15–16 g; 20 mg/kg*0.015–0.016 kg = 0.30–0.32 mg MLT). Xu et al. also teaches administration of melatonin by peritoneal injection.
Regarding claim 22, Wang et al. teaches a method of treating pancreatic cancer in a subject, comprising administering AKBA (claim 6; when R is AcO, the compound is AKBA). Wang et al. also teaches a dosage of 0.05 to 500 mg/kg, noting that “this dosage regimen can be adjusted to provide an optimal treatment response” (para. 0083; AKBA is a compound of formula (I)). Wang et al. does not teach peritoneal administration of AKBA.
Jiang et al. teaches peritoneal administration of AKBA (abstract, “Rats were administered AKBA once every 2 days at doses of 1.5, 3, and 6 mg/kg by intraperitoneal injection).
Because CBD, melatonin, and AKBA are all taught to treat pancreatic cancer individually, and because they are each taught to be administered via the same route (i.e., peritoneally), it would have been obvious to administer these compounds as a composition for treating pancreatic cancer. One of ordinary skill of the art would have been motivated to do so given the teaching of Fliri et al. to make a composition comprising CBD, melatonin and AKBA in light of the teachings of Ferro et al., Xu et al., Wang et al., and Jiang et al. that CBD, melatonin, and AKBA all individually treat pancreatic cancer and can be administered peritoneally.
Furthermore, as discussed before, it would have been prima facie obvious to one of ordinary skill in the art to utilize the amount of CBD as taught by Ferro et al., the amount of melatonin as taught by Xu et al., and the amount of AKBA as taught by Wang et al. as a starting point for optimizing the amount of cannabidiol in a composition comprising CBD, melatonin, and AKBA used to treat pancreatic cancer because dosage is a result-effective variable, i.e. a variable that achieves a recognized result. Therefore, the determination of the optimum or workable dosages in a method comprising administering a combination of CBD, melatonin, and AKBA would have been well within the practice of routine experimentation by the skilled artisan using the teaching of Ferro et al. in view of Xu et al. and Wang et al. Furthermore, absent any evidence demonstrating a patentable difference between the methods in the prior art and the criticality of the claimed dosage range, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan.
Thus, claim 20, directed to the amount of CBD administered, is rejected in view of the dosage taught by Ferro et al. Claim 21, directed to the amount of melatonin administered, is rejected in view of the dosage taught by Xu et al. Claim 22, directed to the amount of AKBA administered, is rejected in view of the dosage taught by Wang et al.
Conclusion
No claims are allowed.
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/OLIVER D HEES/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628