DETAILED ACTION
Claims 1, 37, 40-41, 69, 72-73, 98, 101-102, 145, 175, 218 and 221-225, submitted 18 November 2024, are pending in the application and subject to examination in the instant Office 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 .
Claim Objections
Claims 72 and 221 are objected to because of the following informalities: Claim 72 is objected to on the basis that line 1 of the claim recites “70-72. (Canceled). 72.”. Applicant can overcome this objection separating the canceled claims from the line of the pending claim and appropriately renumbering the canceled claims. In view of the Claims filed 06 September 2024, the correct canceled claims should be claims 70-71. Claim 221 is objected to on the basis that line 1 of the claim recites “219-220 (Canceled) 221.”. Applicant can overcome this objection by separating the canceled claims from the line of the pending claim. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 73, 98, 101, 102, 218, and 221 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.
Regarding claim 102, the phrase in the parenthesis "e.g.," in item “c)” at the third line from the end of claim 102 which renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Additionally, it is also unclear whether the language in the parenthetical is a required claim limitation or not.
Claim 73 recites “c) against the graph of serum levels in Figure 1…”. Claim 73 was previously amended to remove Figure 1. Applicant is reminded that where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” See MPEP 2173.05(s). In the instant case, it would benefit the Applicant to submit a claim amendment that includes the previously amended Figure 1 back into the claim or to amend the claim to reference the Figure incorporated into claim 73 without specifically reference “Figure 1”.
The remaining claims are rejected for depending on a rejected claim and not resolving the aforementioned ambiguity in the parent claim.
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 1, 37, 40-41, 69, 72-73, 98, 101-102, 145, 175, 218, and 221-225 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 the neurodegeneration related to Alzheimer’s disease with cognitive impairment, does not reasonably provide enablement for a method of treating all of the mechanisms associated with neurodegeneration. 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.
Breadth of the Claims
Claims 1, 73, 102, 145, and 175 all recite “A method of treating neurodegeneration…”. As these claims are not drawn to any particular form of neurodegeneration, they can thus be interpreted to encompass all forms and causes of neurodegeneration.
Nature of the Invention
The nature of the invention is within the pharmaceutical arts with regards to the treatment of neurodegeneration in a human subject by administering a pharmaceutical composition comprising the compound of Formula I.
State of the Prior Art
The state of the prior art is what one skilled in the art would have known, at the
time the application was filed, about the subject matter to which the claimed invention
pertains. The relative skill of those in the art refers to the skill of those in the art at the
time the application was filed. See MPEP 2164.05(b). See Pac. Bioscience of Cal., Inc.
v. Oxford Nanopore Techs., Inc., 996 F.3d 1342, 1352, 2021 USPQ2d 519 (Fed. Cir.
2021).
The state of the prior art provides evidence for the degree of predictability in the
art and is related to the amount of direction or guidance needed in the specification as
filed to meet the enablement requirement. The state of the prior art is also related to the
need for working examples in the specification. See MPEP 2165.05(a).
Regarding the treatment of all forms and causes of neurodegeneration, Jellinger ("Basic mechanisms of neurodegeneration: a critical update." Journal of cellular and molecular medicine 14.3 (2010): 457-487.) teaches that neurodegenerative disorders are considered multifactorial and caused by genetic, environmental, and endogenous factors related to aging (pg. 457, Section “Introduction”, Left Col., 1st paragraph). To further build on this, Jellinger states that common pathogenic mechanisms underlying many neurodegenerative disorders include abnormal protein dynamics with misfolding, oxidative stress and formation of free radicals/reactive oxygen species, impaired bioenergetics, fragmentation of neuron Golgi apparatus, disruption of cellular/axonal transport, dysfunction of neurotrophins, and neuroinflammatory/neuroimmune processes (pg. 458, Section “Introduction”, Left Col., 1st paragraph). Pertaining to Alzheimer’s disease, this reference teaches that soluble Aβ oligomers are increased in Alzheimer’s disease in both brain tissue and plasma and their levels correlate with cognitive dysfunction (pg. 459, Section “’Toxic oligomer’ hypothesis”, Left Col., 2nd paragraph). Jellinger also teaches that “ER stress may be involved in some human neuronal diseases, such as AD, PD, prion disease etc. The exact mechanisms and causal effects of ER stress and the proteins involved, however, are poorly understood” (pg. 462, Section “Proteins misfolding and endoplasmic reticulum stress”, Left Col., 1st paragraph).
Regarding the difference in characterizations of neurodegenerative disease, Savelieff et al. ("Development of multifunctional molecules as potential therapeutic candidates for Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis in the last decade." Chemical reviews 119.2 (2018): 1221-1322.) teaches “AD is characterized by the deposition of senile plaques (SPs) and neurofibrillary tangles (NFTs), composed of the aggregates of amyloid-β (Aβ) and hyper phosphorylated tau (ptau), respectively. PD pathology is suggested to be linked to misfolded aggregates of α-synuclein (α-Syn) that accumulate in Lewy bodies. In ALS, aggregates of mutant superoxide dismutase 1 (SOD1), TAR DNA binding protein 43 (TDP-43), fused in sarcoma (FUS), and repeat dipeptides from noncanonical translation of mutant chromosome 9 open reading frame 72 (C9ORF72) are observed (pg. 1222, Section “1.1. Neurodegenerative Diseases”, Left Col., 2nd paragraph). These neurodegenerative diseases share a common characterization in that they cause the loss of neuronal function, however, the aggregate proteins associated with these conditions are different. Thus, one would not expect the same type of treatment response in a subject suffering from ALS as a subject suffering from Alzheimer’s disease even though they are both categorized as neurodegenerative disorders.
With respect to the compound of the instantly claimed invention, Wu et al. ("Activation of the CB2 receptor system reverses amyloid-induced memory deficiency." Neurobiology of aging 34.3 (2013): 791-804.) teaches the compound, known as MDA7, as being a CB2 agonist which has shown to ameliorate the neuroinflammatory process, synaptic dysfunction, and cognitive impairment induced by bilateral microinjection of amyloid-β (Aβ)-1-40 fibrils into the hippocampal CA1 area of rats (Abstract). Wu also teaches that “Because this CB2 agonist prevented Aβ-induced neuroinflammation and its downstream consequence—synaptic plasticity and cognitive impairment—we hypothesize that the CB2 receptor functions in a negative-feedback loop and that its activation can induce Aβ clearance, and blunt neuroinflammatory responses and cognitive impairment induced by Aβ fibrils.” (pg. 792, Section “Introduction”, Right Col., 1st paragraph).
Level of Skill in the Art
The person of ordinary skill in the art is a person who is presumed to have known the relevant art at the relevant time. Factors that may be considered in determining the level of ordinary skill in the art may include: (A) "type of problems encountered in the art;" (B) "prior art solutions to those problems;" (C) "rapidity with which innovations are made;" (D) "sophistication of the technology; and" (E) "educational level of active workers in the field. In a given case, every factor may not be present, and one or more factors may predominate." In re GPAC, 57 F.3d 1573, 1579, 35 USPQ2d 1116, 1121 (Fed. Cir. 1995); Custom Accessories, Inc. v. Jeffrey-Allan Indus., Inc., 807 F.2d 955, 962, 1 USPQ2d 1196, 1201 (Fed. Cir. 1986); Environmental Designs, Ltd. V. Union Oil Co., 713 F.2d 693, 696, 218 USPQ 865, 868 (Fed. Cir. 1983). See MPEP 2141.03 (I).
The invention described pertains to the medical or pharmaceutical arts. One of ordinary skill would be trained in pharmacology, biochemistry, medicine, or a related art field with a Ph. D or other advanced degree in these or other related fields.
Level of Predictability in the Art
The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427, F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art in unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. The scope of the required enablement varies inversely with the degree of predictability involved, but even in unpredictable art, a disclosure of every operable species is not required. A single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements. In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971). However, in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). See MPEP 2164.03. The applicant would need to provide more objective evidence to support the enablement of the aforementioned claims to contrast the unpredictability of the subject matter art.
There is unpredictability in the field of endeavor regarding the currently claimed method of treating all forms and causes of neurodegeneration with a single compound. The unpredictability stems from the lack of prior art to suggest that a single compound can treat all forms and causes of neurodegeneration. Additionally, as detailed above in the State of the Prior Art, the causes of neurodegeneration can be caused by a multitude of aggregate proteins of which are not shown to be overlapping. Moreover, the experiments provided by the Applicant are directed towards the synthesis of the instantly claimed compound and the safety and pharmacokinetics of the multiple ascending dose study.
Amount of Direction Provided by the Inventor
The amount of direction provided by the inventor is correlated by the nature of the unpredictability of the art. Given the context and scope of the claims mentioned above, the inventor failed to provide the necessary amount of direction for one skilled in the art to adequately use the invention across all suggested utility in the broadly stated disease and disorders disclosed above. (See: Section (A) Breadth of the Claims).
As mentioned above, the Applicant has provided guidance for the synthesis of the compound of the invention, as provided in Example 1 found on pages 34-36 of the specification. The Applicant also provided data regarding the safety and pharmacokinetics of the compound in normal volunteers and patients with mild cognitive impairment or early Alzheimer’s disease in Examples 2-8 found on pages 36-60 of the specification.
Quantity of Experimentation Needed to Make or Use the Invention Based on the Content of the Disclosure
As previously stated, the amount of experimentation depends on the art, the predictability of the art, and the direction provided by the inventor. For one skilled in the art to practice the invention as disclosed, the artisan trying to practice Applicant’s claimed invention would be required to undertake unduly burdensome activities including:
Experimentation to demonstrate the treatment of all forms and causes of neurodegeneration as claimed in claims 1, 73, 102, 145, and 175.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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, 37, 40-41, 69, 72-73, 98, 101-102, 145, 175, 218, and 221-225 are rejected under 35 U.S.C. 103 as being unpatentable over Attala et al. (US 2016/0193201 A1) in view of Foss et al. (US 2020/0087288 A1) and Koch-Weser (J. "The serum level approach to individualization of drug dosage." European Journal of Clinical Pharmacology 9.1 (1975): 1-8.).
Attala teaches a method of treating a neurodegenerative disease in a subject, the method comprising administering a CB2 receptor agonist, wherein the CB2 receptor agonist is the compound shown below (Abstract). Attala also teaches wherein the subject is preferably human (paragraph 61).
Compound taught by Attala:
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199
214
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(Claim 17; paragraph 55)
Attala teaches a dose of 15 mg/kg of the compound through intraperitoneal administration. Attala does not teach a similar dose to that of the instantly claimed invention. However, Foss et al. cures this deficiency.
Foss teaches oral formulations pertaining to compounds that modulate CB1 and CB2 wherein the CB2 agonist compound is the compound shown below (Abstract; paragraph 4).
Compound taught by Foss
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149
179
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(paragraph 190)
Foss also teaches wherein the dose of the oral administration of the compounds of the reference are at a range of 5 mg/day to 2 g/day, further specifying that tablets may contain doses at 5 mg to 500 mg and usually around 10 mg to 200 mg (paragraph 167).
While neither of these references teach the increase of the dose administered starting on the 6th day, it would have been prima facie obvious to one skilled in the art of medicine to increase the dosage administered to a subject to assess the safety, tolerability and pharmacokinetics of a novel drug. Therefore, it would have been prima facie obvious to one skilled in the art to combine the teachings of Attala with the teachings of Foss to treat neurodegeneration in a human subject in need thereof. A person having ordinary skill in the art would have had the expectation of success because Foss teaches that the compound of the reference can be used in the treatment of a neurodegenerative disease (Claims 28) and Attala teaches that compound of the reference can be used in the treatment of neurodegenerative diseases including Alzheimer’s disease by stating “The inventors have demonstrated that activation of the central microglial CB2 receptors by MDA7 promote Aβ clearance, ameliorates Aβ-induces glial activation and production of IL-1β, and restores synaptic plasticity, cognition and memory.” (paragraph 16). Thus, it would have been prima facie obvious for a person having ordinary skill in the art, prior to the effective filing date of the instant application, to combine the teachings of Attala with the teachings of Foss to arrive at the instantly claimed invention.
This also reads on instant claim 41, which differs from instant claim 1 in regards to the dosage administered at days 1, 2-5, and 6-28 by further limiting the range of the dose to 90-135 mg for days 1 and 2-5 and 135-202.5 mg for days 6-28, by teaching the dosage range of 5 mg to 500 mg. Claim 102 is also rejected for the above reasons with the only distinction between claim 102 and claim 1 being the dosage administered, which again falls within the range taught by Foss. Claim 175 is also rejected for the above reasons with the distinction between claim 175 and claim 1 lies in point (c) which states in lines 3-5 “increasing the subsequent daily dose to a pharmaceutical composition comprising 125-225% of the amount of the compound of Formula I in the subsequent daily dose administered in step b. The daily dose taught by point (c) of claim 175 would fall between 112.5 mg to 225 mg at an increase of 125%, which falls within the range taught by Foss. The daily dose at 225% would fall within the range of 202.5 mg to 405 mg, which, again, falls within the range taught by Foss.
Claim 73 is rejected on the basis that Foss teaches a method of treating neurodegeneration in a human subject (Claim 28; paragraph 140). Foss also teaches the administration of a dose in a range of 5mg to 500 mg, usually around 10 mg to 200 mg (paragraph 167), which reads on points (a) and (b). Regarding points (c), (d) and (e), while the Attala and Foss references do not teach the measurement, plotting and adjustments of doses to establish a figure of serum levels corresponding to times of measurements, Koch-Weser teaches that “determination of the serum concentration of such compounds can help to guide adjustments of dosage during their therapeutic use.” (Summary). Koch-Weser also provides the motivation for one skilled in the art to follow through with tracking the serum levels of a novel use of a drug by stating that “By measuring the serum level of drugs one bypasses the largest source of individual differences in dose-effect relationships – the pharmacokinetic variation between subjects,” (Summary). Thus, it would have been prima facie obvious for one skilled in the art to measure, plot, and evaluate the blood serum concentration of the claimed compound in a subject through routine optimization to achieve the greatest therapeutic benefit.
Claim 145 is rejected on the basis that Foss teaches a method of treating neurodegeneration in a human subject (Claim 28; paragraph 140). Foss also teaches the administration of a dose in a range of 5mg to 500 mg, usually around 10 mg to 200 mg (paragraph 167), which reads on points (a) and (b). With respect to points (c) and (d) and the maintaining of an AUC of at least 1200 h•ng/mL, for the reasons specified in the rejection of claim 73, it would have again been prima facie obvious for one skilled in the art to maintain an AUC of at least 1200 h•ng/mL to achieve the greatest therapeutic benefit through routine optimization.
Claims 37, 69, 98, 218, 222 and 224 are rejected as Attala teaches wherein the neurodegenerative disease can be Alzheimer’s disease (paragraph 42).
Claims 40, 72, 101, 221, 223 and 225 are rejected on the basis that while Attala does not explicitly teach wherein the neurodegeneration comprises Alzheimer’s disease with cognitive impairment, it’s well known in the art that cognitive impairment is associated with early signs of Alzheimer’s disease. Regarding Alzheimer’s disease, Attala teaches that “The disease course is divided into four stages with progressive patterns of cognitive and functional impairment…” (paragraph 44). Thus, it would have been prima facie obvious for one skilled in the art to try to treat a patient with Alzheimer’s disease with cognitive impairment because Attala also teaches “They found that MDA7 can: (1) promote Aβ clearance…(5) prevent cognitive impairment on spatial memory performance using the Morris water maze test in the Aβ-injected rats.” (paragraph 86). This would also provide one skilled in the art with an expectation of success in the treatment of a human with Alzheimer’s disease with cognitive impairment.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JUSTIN CHRISTOPHER SANCHEZ whose telephone number is (703)756-5336. The examiner can normally be reached Monday -Friday (0730-1700).
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JUSTIN CHRISTOPHER SANCHEZ
Examiner
Art Unit 1622
/J.C.S./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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