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
The instant application is a national stage entry of PCT/IL2021/050605, filed 24 May 2021, which claims priority to U.S. Provisional Patent No. 63/029,504, filed 24 May 2020. The claims are supported by the provisional and are given the effective filing date of 24 May 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/22/2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because in FIG 8 a line cuts through the value above the Cox-1 bar of b Myr rendering it unreadable. The values above the bar graph entries of FIG 10 are grainy and unreadable. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 23-25 and 27-28 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for cell-based methods of contacting immune cells to reduce IL-6 secretion and/or COX expression as shown in the in-vitro macrophage/monocyte assays, does not reasonably provide enablement for therapeutic treatment of subjects across IL-6 or COX-related diseases and patient selection based on undefined “predetermined thresholds of IL-6/COX. 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.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to a method of treating a subject afflicted with an IL-6-related disease, a COX-related disease, or both through the administration of a therapeutically effective amount of the claimed composition. The claims read on treating any IL-6- or COX-related disease in a subject. Thus, the claims are extremely broad.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The prior art depicts IL-6 biology as being context dependent. IL-6 can drive pro-inflammatory or anti-inflammatory effects depending on the signaling pathway (see Hunter), so inhibiting IL-6 is not a one-size-fits-all therapeutic intervention. Different therapeutic strategies produce divergent system-level consequences (e.g., anit-IL-6 antibodies can cause systemic IL-6 accumulation, while IL-6R or trans-selective approaches behave differently), and animal studies show cases where global IL-6 blockade is not beneficial whereas trans-selective inhibition improves survival (see Jones). This underscores the gap between cell-based readouts and organism-level outcomes. Additionally, efficacy is disease-specific not universal. For example, IL-6 inhibition in rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) is well supported, whereas ankylosing spondylitis is not, highlighting that IL-6 related biology does not translate into a general therapeutic rule across all IL-6 mediated diseases (see Schoels).
Chemistry is an unpredictable art (see MPEP 2164.03).
(5) The relative skill of those in the art:
The artisan would be a practitioner working on IL-6 and/or COX-related therapeutics, with knowledge of pharmacology and medicinal chemistry, and familiarity with designing and developing compositions for treating such diseases.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification has provided guidance for cell-based assays including how to culture and differentiate immune cells, apply the composition, and measure IL-6/COX/NO/viability [0124]-[0140].
However, the specification does not provide guidance on how to practice the broad subject treatment methods as claimed. The disclosure generally discusses administration generally, listing acceptable carriers and a laundry list of routes, and defining “therapeutically effective amount” in purely functional terms with the dose determined by the physician. The specification provides no subject-level dosing ranges, or dosing schedules, nor does it provide animal or human treatment data showing that administering the claimed compositions actually treat any IL-6 or COX-related diseases across the sweeping list provided. The “patient selection” step hinges on an IL-6/COX value “above a predetermined threshold,” but the specification gives no threshold values, cut-point methodology, or correlation to clinical benefit beyond a statement that IL-6 can be measured by common immunoassays. Although the claims define “treating” to include outcomes like increasing immune-cell viability or reducing NO in the subject, the specification does not teach how to assess those endpoints at the subject level. Its working guidance is confined to in-vitro/ex-vivo cell assays.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the references above, particularly with regards to the context-dependent nature of IL-6 inhibition and the high unpredictability in the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in the scope of the claims.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 24 is rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claim recites a step of determining the level of secreted IL-6 and/or COX above a predetermined threshold. This judicial exception is not integrated into a practical application because the process of determining the level of IL-6 and/or COX above a threshold is a mental task that lacks additional elements to make the process more than an abstract idea. The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception based on the following analysis.
Regarding claim 24: The claim is directed to a process. Specifically, a process of determining the level of secreted IL-6, COX expression level, or both, above a predetermined threshold.
Step 1: YES. The claim is drawn to a statutory category of a process.
Step 2A, Prong 1: Evaluate Whether the Claim Recites a Judicial Exception
The instant claim recites the process of “determining the level of secreted IL-6, COX expression level, or both.” While the claim uses the word “determining,” they do not recite any concrete or specific steps for how the determination of the levels of IL-6 and/or COX is made, nor is the threshold required for making such determinations disclosed. Thus, the term is construed broadly.
Under USPTO guidance, “determining” can encompass acts that are mental processes, such as observation or recognition of biomarker presence, especially when not tied to any specific laboratory technique or instrumentation. For example, the presence of IL-6 and/or COX in a particular sample could be “determined” by mentally evaluating or observing a previously obtained image or dataset.
Mental processes, including concepts performed in the human mind such as observation, judgement, evaluation, or diagnosis, are considered abstract ideas under the judicial exceptions. Therefore, the claims also fall under the abstract idea exception.
Step 2A, Prong 2: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claim does NOT recite additional steps or elements that integrate the recited judicial exception into a practical application of the exception. While the claim recites “determining the level of secreted IL-6, COX expression level, or both,” these steps are recited at a high level of generality and are not tied to any particular assay, sample type, instrument, transformation, or decision rule. The claim also fails to specify any threshold value used to determine biomarker levels. In the absence of a specified method or threshold, the “determining” step amounts to generic data gathering and lacks concrete steps or guidance for practicing the process.
The method is therefore not integrated into a practical application in a manner required under Step 2A, prong 2. There is no meaningful limitation that applies the identified judicial exception in a way that imposes a significant and specific practical constraint. The claim merely observes a correlation and reports an indication.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
The claim does NOT recite an inventive concept that is sufficient to transform the judicial exception into a patent-eligible application. The additional elements beyond the judicial exception (“determining the level of secreted IL-6, COX expression level, or both”) are conventional, routine, and well-understood activities in the field.
The specification does not describe any novel laboratory techniques, unconventional detection methods, or technological improvements associated with the determination of the IL-6 and/or COX levels. Nor does it provide evidence that the claimed method requires anything more than standard diagnostic reasoning or generic detection methods common in the art. This is exemplified by the teachings of [0084]-[0089].
The claim therefore amounts to no more than (i) routine measurement of IL-6 and/or COX and (ii) a mental evaluation of the result. These are well-understood, routine, and conventional diagnostic activities that do not add significantly more than the judicial exception. The claim therefore lacks an inventive concept and is not patent-eligible.
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, 3-8, 13, 14, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Eyal (WO 2017/158539 A1, found in IDS submitted 04/11/2024).
Eyal discloses multi-cannabinoid compositions containing CBD, CBDa, THC, and THCa with independent minimum concentrations by weight and selectable concentration bands for each component (e.g., CBD/CBDa and THC/THCa each ≥5-10 wt%, and in some embodiments ≥5-40 wt%, see Abstract, [0007], Claims 1, 3, and 4). Eyal further teaches compositions comprising at least five cannabinoids and the cannabinoids are selected from THC, THCa, CBD, CBDa, cannabigerol (CBG), THCV, THCVa, CBN, or CBNa (see [0047]). The reference also discloses that the composition comprises a primary terpene which is selected from the group which includes b-caryophyllene, and b-myrcene (see [0004] and [0008], Claim 8) and a non-terpene carrier which is cellulose (see [0004], [0006], Claim 1, and Claim 3), reading on claims 5, 7, 13, and 16. The weight/weight ratio of the terpene to cannabinoid is about 0.05 to 1.0, which is equivalent to a range of 1:20 to 1:1 (see [0004]).
The artisan would have a background in pharmacology, biochemistry, or medicinal chemistry, with experience in developing or evaluating cannabinoid-containing formulations and would understand cytokine modulation pathways such as IL-6. The authors of the references cited by the Examiner possess comparable expertise and are representative of the level of ordinary skill in the art.
Although Eyal does not explicitly disclose numeric ratios for THC:THCa, CBD:CBDa, (CBD+CBDa):(THC+THCa), or (THC/CBD):additional cannabinoids, it provides minimum threshold amounts for each component. At those minima, THC:THCa:CBD:CBDa are presented at 1:1:1:1, and the terpene:cannabinoid ratio reaches 1:1. These values overlap or are encompassed by the instant claims’ recited ratio windows for claims 1, 3, 4, 6, 8, and 14. Where a claimed range overlaps a prior-art range, a prima facie case of obviousness is established absent evidence of criticality or unexpected results; likewise, selection of specific proportions within disclosed bands is a predictable optimization of known variables.
Claims 1 and 20-23 are rejected under 35 U.S.C. 103 as being unpatentable over Eyal in view of Newton (Newton, C et al. “The role of macrophages in THC-induced alteration of the cytokine network.” Advances in experimental medicine and biology vol. 437 (1998): 207-14. doi:10.1007/978-1-4615-5347-2_23).
Eyal teaches the composition of instant claim 1. The proceeding discussion is incorporated by reference into this rejection. Eyal does not teach a method for reducing or inhibiting IL-6 secretion by and immune cell through contacting said immune cell with an effective amount of the composition, wherein the immune cell comprises a monocyte and/or macrophage, wherein the contacting is done in-vivo, ex-vivo, or in-vitro.
Newton teaches that when THC is applied in-vitro to primary macrophage cultures, the cannabinoid suppresses IL-6 secretion, reading on instant claims 20-23 (see Abstract pg. 207 and Discussion pgs. 212-213).
The artisan would have a background in pharmacology, biochemistry, or medicinal chemistry, with experience in developing or evaluating cannabinoid-containing formulations and would understand cytokine modulation pathways such as IL-6. The authors of the references cited by the Examiner possess comparable expertise and are representative of the level of ordinary skill in the art. The artisan would have been motivated to use Elay’s compositions in a method to reduce or inhibit IL-6 secretion by immune cells because THC is known to suppress IL-6 secretion in macrophages in vitro. Given that Elay includes THC among its cannabinoid components, the artisan would have reasonably expected that administering Elay’s composition containing THC at an operative amount would likewise suppress macrophage IL-6 secretion.
Claims 1 and 2 are rejected under 35 U.S.C. 103 as being unpatentable over Eyal in view of McPartland (McPartland, John M et al. “Affinity and Efficacy Studies of Tetrahydrocannabinolic Acid A at Cannabinoid Receptor Types One and Two.” Cannabis and cannabinoid research vol. 2,1 87-95. 1 May. 2017, doi:10.1089/can.2016.0032) and Lewis-Bakker (Lewis-Bakker, Melissa M et al. “Extractions of Medical Cannabis Cultivars and the Role of Decarboxylation in Optimal Receptor Responses.” Cannabis and cannabinoid research vol. 4,3 183-194. 23 Sep. 2019, doi:10.1089/can.2018.0067).
Eyal teaches the composition of instant claim 1. The proceeding discussion is incorporated by reference into this rejection. Eyal does not explicitly teach the ratio of THC:THCa to be between 2:1 and 2.5:1.
McPartland teaches THCa decarboxylates to THC under processing and storage conditions leading to variable in-situ THC generation (pg. 88, left Col, first para.).
Lewis-Bakker teaches that chemical consistency and associated biological activities of medical cannabis products are critical for pharmaceutical grade products and for patient care (pg. 188, left Col, second para).
Those of relevant skill in the art are those with the level of skill of the inventors of the references cited to support the Examiner’s positions.
The artisan would have been motivated to adapt Eyal’s compositions to favor THC over THCa, because THCa decarboxylates to THC under processing and storage conditions. Increasing the initial THC relative to THCa would reduce in-situ THC generation from THCa and thereby improve does consistency of the active THC in the composition. Thus, the THC:THCa proportion constitutes an optimizable parameter, and the recited ratio is a predictable selection within the prior-art range of routine optimization.
Claims 1 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Eyal and Kozela (Kozela, Ewa et al. “Cannabinoids Delta(9)-tetrahydrocannabinol and cannabidiol differentially inhibit the lipopolysaccharide-activated NF-kappaB and interferon-beta/STAT proinflammatory pathways in BV-2 microglial cells.” The Journal of biological chemistry vol. 285,3 (2010): 1616-26. doi:10.1074/jbc.M109.069294).
Eyal teaches the composition of instant claim 1. The proceeding discussion is incorporated by reference into this rejection. Eyal does not explicitly teach the total concentration range of the cannabinoids in the composition.
Kozela teaches concentration dependent suppression of IL-6 by cannabinoids in immune cells. The reference discloses that pretreatment of the cells with THC or CBD (at 1, 5, or 10 mM) signigicantly and dose-dependently decreased the amount of released IL-1b and IL-6 (pg. 1618, right Col, third paragraph). Kozela further teaches the following: The release of IL-6 was more strongly inhibited by CBD than by THC. The lowest dose of CBD used (1 µM) reduced the release of IL-6 from LPS-activated microglia by ~25% (an effect comparable with that achieved with 5 mM THC), whereas 5 and 10 µM reduced the release of IL-6 by 85 ± 2 and 91 ± 1%, respectively (Fig. 1B). Both cannabinoids decreased the level of LPS-induced release of IFN. At 10 µM, THC and CBD reduced the LPS-induced release of IFN by 34 ± 12 and 37 ± 7%, respectively (Fig. 2) (pg. 1618, right Col, third paragraph). These teachings highlight that the cannabinoid concentration is a result-effective variable for IL-6 suppression.
Those of relevant skill in the art are those with the level of skill of the inventors of the references cited to support the Examiner’s positions.
The artisan would have been motivated to modify Eyal’s composition so that the total cannabinoid concentration is effective to inhibit IL-6 secretion from immune cells. Kozela teaches a clear concentration response, reporting that CBD at ~10 mM suppressed IL-6 release by ~90% in immune cells. In view of this, the artisan would have reasonably expected that adjusting the CBD (and total cannabinoid concentration) to at or modestly above this level would achieve the desired IL-6 inhibition, with the exact concentration being a result-effective variable subject to routine optimization.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONNOR KENNEDY ENGLISH whose telephone number is (571)270-0813. The examiner can normally be reached Monday Friday, 8 a.m. 5 p.m. ET..
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/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625