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 .
Election/Restrictions
REQUIREMENT FOR UNITY OF INVENTION
As provided in 37 CFR 1.475(a), a national stage application shall relate to one invention only or to a group of inventions so linked as to form a single general inventive concept (“requirement of unity of invention”). Where a group of inventions is claimed in a national stage application, the requirement of unity of invention shall be fulfilled only when there is a technical relationship among those inventions involving one or more of the same or corresponding special technical features. The expression “special technical features” shall mean those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art.
The determination whether a group of inventions is so linked as to form a single general inventive concept shall be made without regard to whether the inventions are claimed in separate claims or as alternatives within a single claim. See 37 CFR 1.475(e).
When Claims Are Directed to Multiple Categories of Inventions:
As provided in 37 CFR 1.475 (b), a national stage application containing claims to different categories of invention will be considered to have unity of invention if the claims are drawn only to one of the following combinations of categories:
(1) A product and a process specially adapted for the manufacture of said product; or
(2) A product and a process of use of said product; or
(3) A product, a process specially adapted for the manufacture of the said product, and a use of the said product; or
(4) A process and an apparatus or means specifically designed for carrying out the said process; or
(5) A product, a process specially adapted for the manufacture of the said product, and an apparatus or means specifically designed for carrying out the said process.
Otherwise, unity of invention might not be present. See 37 CFR 1.475 (c).
This application contains claims directed to more than one species of the generic invention. These species are deemed to lack unity of invention because they are not so linked as to form a single general inventive concept under PCT Rule 13.1.
Restriction is required under 35 U.S.C. 121 and 372.
This application contains the following inventions or groups of inventions which are not so linked as to form a single general inventive concept under PCT Rule 13.1.
In accordance with 37 CFR 1.499, applicant is required, in reply to this action, to elect a single invention to which the claims must be restricted.
The species are as follows:
Elect an inhibitor of BACE1, for example a small molecule inhibitor as listed in claim 3, and a specific neurodegenerative condition.
Applicant is required, in reply to this action, to elect a single species to which the claims shall be restricted if no generic claim is finally held to be allowable. The reply must also identify the claims readable on the elected species, including any claims subsequently added. An argument that a claim is allowable or that all claims are generic is considered non-responsive unless accompanied by an election.
Upon the allowance of a generic claim, applicant will be entitled to consideration of claims to additional species which are written in dependent form or otherwise require all the limitations of an allowed generic claim. Currently, the following claim is generic: independent claim 1 is generic to the neurodegenerative condition associated with loss of motor function and the inhibitor of BACE1.
The groups of inventions listed above do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special technical features for the following reasons:
Inhibitor of BACE1 and the neurodegenerative condition lack unity of invention because even though the inventions of these groups require the technical feature of the inhibitor of BACE1 and the patient of the population having a neurodegenerative condition associated with loss of motor function, this technical feature is not a special technical feature as it does not make a contribution over the prior art in view of Rueeger et al. (J. Med. Chem. 2021, 64, 4677–4696 ). Rueeger et al. discloses the mechanism by which the aspartic protease (BACE1) initiates the β-secretase pathway that generates amyloid- β. Accumulation of amyloid- β in parenchymal plaques is a pathological hallmark of Alzheimer’s disease (Introduction). Additionally, Rueeger et al. discloses compound 54, NB-360 as having the best in vitro profile and the most robust brain Aβ peptide reduction in rats (Conclusions).
During a telephone conversation with Janice DeYoung on 08/19/2026 a provisional election was made to prosecute the invention of small molecule inhibitor of BACE1, MBI-9; and neurodegenerative condition, spinocerebellar ataxia type 1, SCA1, claims 1-3, 9-11. Affirmation of this election must be made by applicant in replying to this Office action. Claims 4-8, 12-14 withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected species.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
The examiner has required restriction between product or apparatus claims and process claims. Where applicant elects claims directed to the product/apparatus, and all product/apparatus claims are subsequently found allowable, withdrawn process claims that include all the limitations of the allowable product/apparatus claims should be considered for rejoinder. All claims directed to a nonelected process invention must include all the limitations of an allowable product/apparatus claim for that process invention to be rejoined.
In the event of rejoinder, the requirement for restriction between the product/apparatus claims and the rejoined process claims will be withdrawn, and the rejoined process claims will be fully examined for patentability in accordance with 37 CFR 1.104. Thus, to be allowable, the rejoined claims must meet all criteria for patentability including the requirements of 35 U.S.C. 101, 102, 103 and 112. Until all claims to the elected product/apparatus are found allowable, an otherwise proper restriction requirement between product/apparatus claims and process claims may be maintained. Withdrawn process claims that are not commensurate in scope with an allowable product/apparatus claim will not be rejoined. See MPEP § 821.04. Additionally, in order for rejoinder to occur, applicant is advised that the process claims should be amended during prosecution to require the limitations of the product/apparatus claims. Failure to do so may result in no rejoinder. Further, note that the prohibition against double patenting rejections of 35 U.S.C. 121 does not apply where the restriction requirement is withdrawn by the examiner before the patent issues. See MPEP § 804.01.
Restriction Election
Pursuant to MPEP 803.02, the Examiner will start the search with the elected specie and expand accordingly. In this case, the elected specie was identified in the art (see rejections below).
Status of Claims
Claims 1-3, 9-11 are under examination.
Priority
Instant application 18/868,526 filed 11/22/2024 claims priority as follows:
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Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. 63/345,895, filed on 05/25/2022.
Information Disclosure Statement
All references from IDS received 11/22/2024 have been considered unless marked with a strikethrough.
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.
Claim 3 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 3 provides the name of the elected small molecule inhibitor MBI-9, however, the structure associated with the name is not provided, therefore the examiner cannot determine the metes and bounds of the claim.
Improper Markush Rejection
Claims 1 and 2 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
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The Markush grouping of inhibitor of BACE1 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: biomolecules (biologics) differ from small molecules based on size and manufacturing process. Further, biologics may bind to different protein subunits vs molecular inhibitors functioning in a different manner. Examples of biologics include hormones, vaccines, monoclonal antibodies, proteins, etc. Examples of small molecules include aspirin, felbamate, procaine, etc. Table 1 (Markurvet, F.D., Medicine in Drug Discovery, 2021, 9, 100075, p.2, Table 1, shown below) depicts major differences between biologics and small molecules.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 § 102
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 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.
Claim 1 and 2 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rueeger et al. (J. Med. Chem. 2021, 64, 4677-4696).
This rejection applies to the expanded specie, wherein the BACE1 molecule is NB-360 and the disease is Alzheimer’s.
Rueeger et al. discloses Alzheimer’s disease, which based on at least the instant specification is associated with loss of motor function, as the world’s leading cause of dementia and the most prevalent neurodegenerative disease. It teaches how accumulation of amyloid-β (Aβ) in parenchymal plaques and the brain vasculature and hyperphosphorylated tau in neurofibrillary tangles is a pathological hallmark of the disease (p. 4677, Introduction). Moreover, Rueeger et al. discloses a small molecule inhibitor of BACE1, compound 54, NB-360, able to reduce significantly Aβ levels in mice, rats, and dogs in acute and chronic treatment regimens (Abstract).
Therefore, claims 1 and 2 are anticipated by Rueeger et al.
Claims 1-3 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tallon et al. (Neurotherapeutics 2020, 17, 973-988; made of record in the IDS).
This rejection applies to the elected compound MBi-9 and the expanded patient population of nerve regeneration.
Tallon et al. discloses the investigation of a BACE1 inhibitor to enhance nerve regeneration in models of neurodegenerative disease by employing the SOD1G93A mouse model of amyotrophic lateral sclerosis (ALS) (Introduction). MBi-9 is a potent inhibitor of human BACE1 enzyme in vitro (Ki = 1.5 nM) and in cells (HEK293-APPswe/Lon IC50 = 2.22 nM) (p. 974, Drug Information). Additionally, Tallon et al. performed a consistent dosing over a 10-day period with all doses tested (1 mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg) (p. 977, Results, In Vivo section).
Therefore, claims 1-3 are anticipated by Tallon et al.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 9-11 are rejected under 35 U.S.C. 103 as being unpatentable over Rueeger et al. (J. Med. Chem. 2021, 64, 4677-4696) in view of Tejwani et al. (Cell. Mol. Life Sci. 2020, 77, 4015-4029; made of record in the IDS) and further in view of Tallon et al. (Neurotherapeutics 2020, 17, 973-988; made of record in the IDS).
This rejection applies to the elected specie MBi-9 and the patient population having spinocerebellar ataxia type 1, SCA1.
Rueeger et al. discloses the involvement of the membrane-bound aspartic protease BACE1 in the generation of amyloid-β (Aβ). Aβ is generated in the β-secretase pathway from the large transmembrane β-amyloid precursor protein (APP). The membrane-bound aspartic protease BACE1 initiates the pathway by cleaving APP at position one of Aβ, generating the secreted amino-terminal part of APP (sAPPβ) as well as the carboxy-terminal fragment C99. This transmembrane fragment is further cleaved by ɣ-secretase leading to Aβ. Accumulation of Aβ in parenchymal plaques and the brain vasculature is a pathological hallmark of Alzheimer’s disease. Neuroinflammation, driven by plaque-activated microglia and astrocytes, is a likely mediator between amyloid pathology and synaptic and neuronal dysfunction and neuron loss. (Introduction). Additionally, Rueeger et al. discloses the synthesis and optimization of compound 54, NB-360, able to reduce significantly Aβ levels in mice, rats, and dogs in acute and chronic treatment regimens (Title & Abstract).
Tallon et al. discloses levels of β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) shown to regulate peripheral nerve regeneration. Investigation of BACE1 inhibitor was used in a well-characterized model of motor disease, the SOD1G93A mouse model of amyotrophic lateral sclerosis (ALS), to examine the impact of BACE1 inhibition in neurodegenerative disease (Introduction). MBi-9 is a potent inhibitor of human BACE1 enzyme in vitro (Ki = 1.5 nM) and in cells (HEK293-APPswe/Lon IC50 = 2.22 nM) (p. 974, Drug Information). Additionally, Tallon et al. performed a consistent dosing over a 10-day period with all doses tested (1 mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg) (p. 977, Results, In Vivo section).
Tejwani et al. describes hereditary cerebellar ataxias which primarily result in a progressive degeneration of the tissues involved in the coordination of movement. Hereditary ataxias have been classified based on the mode of inheritance, the spinocerebellar ataxias (SCAs), inherited in an autosomal dominant manner, and the recessive ataxias, which include the spinocerebellar ataxia, autosomal recessive disorders (SCARs). Among the autosomal dominantly inherited SCAs, mutations in many functionally disparate genes have been identified. It was determined that a subset of highly penetrant SCAs was due to similar polyglutamine (polyQ) repeat expansion mutations, which were later named SCA1, SCA2, SCA3/Machado-Joseph Disease (MJD), SCA6, SCA7, SCA17, and dentatorubral-pallidoluysian atrophy (DRPLA) (p. 4015-16, Introduction).
Additionally, Tejwani et al. teaches the underlying genetic cause of spinocerebellar ataxia type 1 (SCA1) being the presence of an unstable CAG repeat identified in ATXN1 (p. 4016, SCA1 section). Beyond its causal role in SCA1, ataxin-1 (ATXN1) has been implicated in other neurodegenerative diseases. Intermediate length polyQ expansions of ataxin-1 (≥32 repeats) that do not expand to the pathogenic SCA-1 causing length are associated with a greater risk for developing sporadic amyotrophic lateral sclerosis (sALS). Furthermore, follow-up studies in mice have revealed that loss of Atxn1 may contribute to AD-related phenotypes through increasing the proteolytic cleavage of amyloid precursor protein (APP) via an increase in the transcription of the BACE1, encoding the β-secretase enzyme (p. 4018, Ataxin-1 section, col. 2). Tejwani et al. also teaches that neurons within the cerebellum and brainstem degenerate through the course of SCA1, but the contribution of non-neuronal cells to neurodegenerative diseases, such as ALS, Alzheimer’s disease and Hungtington’s disease is becoming more apparent. In the case of SCA1, transgenic mice in which polyQ-expanded ataxin-1 expression is limited to Purkinje cells, as well as SCA1 knock-in mice, display an early activation of astrocytes and microglia, suggesting a non-cell-autonomous induction of neuroinflammation (p.4022, Regional section, col. 1).
With respect to claims 1-3,
Rueegers et al. teaches the development and synthesis of a small molecule inhibitor of BACE1, NB-360; as well as the involvement of BACE1 enzyme in the pathology of Alzheimer’s disease.
Rueegers et al. fails to teach the linkage of BACE1 to SCA1, or MBi-9.
Tallon et al. teaches experimental studies on the SOD1G93A mouse model of amyotrophic lateral sclerosis (ALS) using an inhibitor of BACE1 enzyme, MBi-9. Particularly, it teaches consistent dosing over a 10-day period with all doses tested (1 mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg).
Tejwani et al. teaches the underlying cause of the neurodegenerative condition, spinocerebellar ataxia type 1 (SCA1), the presence of an unstable CAG repeat identified in ATXN1.
Thus, Tallon et al. links BACE1 to the SOD1G93A model of ALS and teaches the alternative BACE1 inhibitor MBi-9.
Applying KSR prong B, it would have been prima facie obvious to substitute one BACE1 inhibitor for another to treat either ALS and/or Alzheimer’s disease.
The combination fails to teach using a BACE1 inhibitor to treat spinocerebellar ataxia type 1, SCA1.
However, Tejwani et al. establishes the link between BACE1 inhibition and treating spinocerebellar ataxia 1, such that one would predict that BACE1 inhibition would be expected to treat the disease.
Applying KSR prong B, it would have been prima facie obvious to substitute one disease known to be treated with a BACE1 inhibitor with another disease linked to BACE1 inhibitors. One would reasonably expect success because MBi-9 is a BACE1 inhibitor and BACE1 inhibition is linked to spinocerebellar ataxia 1.
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art, to have use the knowledge from Rueeger et al. of BACE1 enzyme involvement in the pathology of a neurodegenerative disease such as Alzheimer’s and combine it with the information provided by Tallon et al. about BACE1 inhibitor, MBi-9 and its manner of administration in treating ALS, to treat the neurodegenerative condition, SCA1 from Tejwani et al. All these neurodegenerative diseases are defined by a loss of particular populations of neurons, but the contribution of non-neuronal cells to these disorders is becoming more apparent, as mentioned by both Rueeger et al. and Tejwani et al. with respect to neuroinflammation being prompted by the activation of astrocytes and microglia (Introduction; p. 4022, Regional section, respectively). These neurodegenerative conditions have some overlapped neurodegeneration mechanisms, therefore, there is an expectation that a BACE1 inhibitor use for a condition such as Alzheimer’s could be used for the treatment of spinocerebellar ataxia type 1.
With respect to claim 9-11
Rueegers et al. teaches the involvement of BACE1 enzyme in the pathology of Alzheimer’s disease and the development of an BACE1 inhibitor.
Rueegers et al. fails to teach wherein the neurodegenerative condition is a progressive loss of motor function and coordination, or wherein the condition is spinocerebellar ataxia (SCA) or wherein the SCA is a polyglutamine SCA, optionally SCA1.
Tejwani et al. teaches hereditary cerebellar ataxias that result primarily in a progressive degeneration of the tissues involved in the coordination of movement. It teaches spinocerebellar ataxia, particularly a subset characterized by a polyglutamine (polyQ) repeat expansion mutation, type 1 (SCA1), this being the elected species by the applicant. Moreover, it teaches loss of ATXN1 gene possibly contributing to AD-related phenotypes through increasing the proteolytic cleavage of amyloid precursor protein (APP) via an increase in the transcription of the BACE1, encoding the β-secretase enzyme.
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art, to have use the knowledge gathered from Tejwani et al. about SCA1 and ATXN1 in combination with the information provided about Alzheimer’s and BACE1, and use it with the mechanism of action of the BACE1 enzyme described in Rueeger et al. to accomplish the method of treating the neurodegenerative condition spinocerebellar ataxia type 1 described in claims 9-11.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CINDY BAGNAL whose telephone number is (571)270-1080. The examiner can normally be reached M-F 8:00 am-4:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/C.B./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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