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 Status
Pursuant to the preliminary amendment dated 14 Mar 2024, claims 1-4 and 8-11 are canceled by the applicant. Claims 5-7 and 12-24 are pending.
Restriction Requirement
Restriction to one of the following inventions is required under 35 U.S.C. § 121:
Claims 5-7 and 12-16, drawn to a method of screening a compound for treating Alzheimer’s disease, classified in A01K 2267/0312.
Claims 17-19, drawn to a method of modifying a mouse genome, classified in A01K 67/0278.
Claims 20-24, drawn to a method of modifying a mouse stem cell, classified in A01K 67/0278.
The inventions are independent or distinct from each other because:
Inventions I and II-III are directed to related processes. The related inventions are distinct if: (1) the inventions as claimed are either not capable of use together or can have a materially different design, mode of operation, function, or effect; (2) the inventions do not overlap in scope, i.e., are mutually exclusive; and (3) the inventions as claimed are not obvious variants. See MPEP § 806.05(j). In the instant case, Inventions II and III may be used to generate mice for purposes other than screening compounds for Alzheimer’s disease, such as studying the functions of humanized APOE4 and mouse Trem2 R47H in vivo. Additionally, Inventions II and III can be performed in single or isolated cells without generating a mouse with a modified genome in every cell. Furthermore, the inventions as claimed do not encompass overlapping subject matter and there is nothing of record to show them to be obvious variants.
Inventions II and III are directed to related processes. The related inventions are distinct if: (1) the inventions as claimed are either not capable of use together or can have a materially different design, mode of operation, function, or effect; (2) the inventions do not overlap in scope, i.e., are mutually exclusive; and (3) the inventions as claimed are not obvious variants. See MPEP § 806.05(j). In the instant case, Invention II can be performed without modifying a stem cell. Additionally, Invention III can be performed without modifying the genome, such as by transfecting a transient expression vector. Furthermore, the inventions as claimed do not encompass overlapping subject matter and there is nothing of record to show them to be obvious variants.
Restriction for examination purposes as indicated is proper because all the inventions listed in this action are independent or distinct for the reasons given above and there would be a serious search and/or examination burden if restriction were not required because one or more of the following reasons apply:
(A) Separate classification thereof;
(B) A separate status in the art when they are classifiable together; and
(C) A different field of search.
Applicant is advised that the reply to this requirement to be complete must include (i) an election of an invention to be examined, even though the requirement may be traversed (37 CFR 1.143), and (ii) identification of the claims encompassing the elected invention.
The election of an invention may be made with or without traverse. To reserve a right to petition, the election must be made with traverse. If the reply does not distinctly and specifically point out supposed errors in the restriction requirement, the election shall be treated as an election without traverse. Traversal must be presented at the time of election in order to be considered timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are added after the election, applicant must indicate which of these claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. § 103 of the other invention.
During a telephone conversation with Heather J. DiPietrantonio, PhD on 04 Mar 2026, a provisional election was made without traverse to prosecute the invention of Group I, claims 5-7 and 12-16. Affirmation of this election must be made by applicant in replying to this Office action. Claims 17-24 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
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).
Information Disclosure Statement
The information disclosure statement (IDS) submitted 14 Jun 2024 is in compliance with the provisions of 37 CFR 1.97 and 1.98. The IDS cites over 140 individual references, representing thousands of pages of publications and other documents. Accordingly, the IDS has been considered by the examiner insofar as document titles relate to the claimed invention.
Claim Objections
Claims 5 and 16 are objected to because of the following informalities:
Regarding claim 5, an endogenous allele, by definition, cannot be genetically modified. An allele may, however, be modified at an endogenous locus.
Regarding claim 16, several of the differentially expressed genes are listed redundantly.
Appropriate correction is required.
Claim Rejections - 35 USC § 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.
Claims 5-7 and 12-16 are rejected under 35 U.S.C. § 112(a) as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). 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 ‘undue’, not ‘experimentation.’” (Wands, 8 USPQ2d 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). When determining whether a specification meets the enablement requirement, some of the factors to be analyzed are: (1) the breadth of the claims, (2) the nature of the invention, (3) the state of the prior art, (4) the level of one of ordinary skill in the art, (5) the level of predictability in the art, (6) the amount of direction provided by the inventor, (7) the existence of working examples, and (8) whether the quantity of any necessary experimentation to make and use the invention based on the content of the disclosure is undue (Wands). While all of these factors are considered, those sufficient for establishing a prima facie case are discussed below.
Claims 5-7 and 12-16 are drawn to a method of screening compounds for use in treating non-familial late-onset Alzheimer’s disease. The method recites steps of (a) administering a compound to a transgenic mouse homozygous for humanized APOE4 and mouse Trem2 R47H as a model for non-familial late-onset Alzheimer’s disease and (b) assessing the effect of the compound on one or more signs of non-familial late-onset Alzheimer’s disease. However, the method does not recite active steps for what comparisons are being made, specify the characteristic(s) by which the compounds are being screened, or specify what results would indicate that a screened compound has a given characteristic.
Nature of the invention
The nature of the invention relates to use of a mouse model of non-familial late-onset Alzheimer’s disease comprising transgenes of APOE4 and Trem2 variants found to be strong risk factors for development of the disease to screen for candidate compounds for treating the disease.
Existence of working examples
Claim 5 recites that the mouse “exhibits one or more signs of non-familial late-onset Alzheimer’s disease associated with expression of the humanized APOE4p and the modified mouse TREM2p”. The specification teaches “[s]uch signs and symptoms include, but are not limited to, any one or more of” an increase in microglia in the brain, increase in amyloid plaques in the brain, increase in tau aggregates in the brain, increased inflammation in the brain, synaptic and/or neuronal loss, cognitive deficit, frailty, blood flow deficit in the brain, difference in disease biomarkers, cerebrovascular leakage, and changes in lipoproteins and/or cholesterol relative to APOE3-expressing control mice (par. 134). Of these signs and symptoms, the specification only provides support for changes in apolipoproteins, cholesterol, inflammation, and cerebrovascular leakage (par. 165-185 and Fig. 3-4). The specification additionally provides changes in expression of genes associated with other pathological processes of the disease, but does not indicate whether those pathological processes are altered in the mouse model, whether the degree of change in expression is sufficient to predict alteration, or what, if any, changes in gene expression are indicative of success for a screened compound (par. 186-192 and Table I). It is noted that brain samples from the mice were stained with Thioflavin S, a histological stain for identifying amyloid plaques, but the specification did not report whether there were differences in Thioflavin S staining between B6J.APOE4/Trem2 mice and control mice (par. 168-172). No examples are provided demonstrating the ability of a candidate treatment to reverse signs or symptoms of the disease associated with the phenotype.
Amount of direction provided by the inventor
The specification fails to provide guidance with regard to how one of ordinary skill in the art would carry out the assessment of claim 5 step (b). The specification provides that assessing the effect “...preferably includes comparing the result of the assessment with a suitable control, such as, but not limited to, the effect of the compound on a control...mouse” (par. 133). The specification further provides that signs or symptoms “can be assessed by methods well-known in the art including, but not limited to, immunoassay, nucleic acid assay, histochemical staining, cognitive assays, in vivo imaging, physical assessment of the animals, cerebrovascular leakage assessment, and morphological assessment of tissues and/or cells” (par. 138). These definitions provided in the specification are not limiting definitions and do not provide active steps for assessing the effect or determining an outcome.
The specification also fails to provide a nexus between the phenotype of the mouse model and the disease. With regard to lipoprotein and cholesterol, the specification states that “[a]lthough the mechanisms by which the APOE4 variant increase the risk for Alzheimer’s disease is not known, these effects on altered metabolism are thought to play a role.” (par. 178). With regard to inflammation and cerebrovascular leakage, the specification states “[v]ascular damage may be a key aspect of late-onset Alzheimer’s disease.” Speculative roles for disease processes and risk factors do not provide a concrete phenotype by which a skilled artisan may assess a candidate therapy for treating a disease. Without a clear connection between the mouse phenotype and disease features, it is unclear what results would be indicative of success or failure for a screened compound.
State of the prior art and Unpredictability in the art
As of the earliest effective filing date of the claimed invention, 21 Mar 2017, no drug had been approved for the treatment of Alzheimer’s and most of clinical trials of disease-modifying therapies had failed (K. Suzuki, Proc Jpn Acad Ser B Phys Biol Sci, 2011, p. 765). Onos (K.D. Onos, et al., Brain Res Bull, 2016, cited in IDS) teaches that a significant gap exists in translating preclinical data for Alzheimer’s disease (p. 9). While the list of pathological features of the disease detailed in the specification in par. 134 are supported in the art, the ability of candidate therapies to sufficiently alter those features in patients has been remarkably unsuccessful as of the earliest effective filing date. Together, these indicate that the art can provide little guidance to support use of the claimed invention.
Conclusions
The specification does not provide a concrete phenotype for the mouse model clearly connected to the disease sufficient to screen for potential therapeutics. A skilled artisan would face an unreasonable burden of experimentation in having to further characterize the phenotype of the mouse to identify modifiable pathological features in the model predictive of therapeutic success before attempting to use the claimed method of screening a compound. Compounds that alter a phenotype so loosely connected to the disease are merely candidates to be characterized further. The claim should recite active steps and what result would be indicative that the screened compound is a candidate compound for treating non-familial late-onset Alzheimer’s disease.
Claims 12-13 are rejected under 35 U.S.C. § 112(a) as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed, had possession of the claimed invention.
Claim 12 recites that the nucleic acid encoding humanized APOE4 may be “the complement of a nucleic acid that hybridizes to the nucleic acid sequence of SEQ ID NO: 2 under highly stringent hybridization conditions.” Similarly, claim 13 recites that the nucleic acid encoding Trem2 R47H may be “the complement of a nucleic acid that hybridizes to the nucleic acid sequence of SEQ ID NO: 4 under highly stringent hybridization conditions.” The specification provides that “nucleic acids having about 85-100% complementarity are considered highly complementary and hybridize under high stringency conditions” (par. 51). Therefore, the breadth of claims 12-13 encompasses a genus of nucleic acids for each claim having up to 15% non-complementarity with the respective recited SEQ IDs that can hybridize under highly stringent hybridization conditions.
The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, such as physical and/or chemical properties, functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show that the inventor was in possession of the claimed genus. See MPEP § 2163(II)(A).
Regarding claim 12, Windham (I.A. Windham and S. Cohen, Trends Cell Biol, 2024) teaches that a high-resolution structure of the full-length APOE has not been determined and that a full-length NMR structure has only been resolved for a lipid-free protein, and therefore is unclear if that structure is representative of a lipid-bound protein in vivo (p. 339). Windham further teaches that the mechanism by which the single amino acid substitution in APOE4 as compared to APOE3 increases risk of Alzheimer’s disease is not completely understood (pp. 342-343). Therefore, the structural requirements for APOE4 are not predictable. Protein folding and function is highly dependent on sequence, and even conservative amino acid variations can dramatically impact protein structure. The task, then, of predicting tolerability of amino acid substitutions becomes guesswork. Therefore, even after the earliest effective filing date, a skilled artisan would be unable to predict whether a species of nucleic acid sequence encompassed by claim 12 encodes for an APOE4 protein that gives rise to the genetically modified mouse exhibiting one or more signs of non-familial late-onset Alzheimer’s disease as required by claim 1.
Regarding claim 13, Ulrich (J.D. Ulrich and D.M. Holtzman, ACS Chem Neurosci, 2016) teaches that the mechanisms by which Trem2 variants contribute to Alzheimer’s disease risk were in their infancy, but evidence suggested that the R47H variant conferred a loss of function to Trem2 (pp. 421-422). Ulrich further teaches that in contrast, Trem2 knockout has a protective effect in models of Alzheimer’s disease (pp. 421-422). Variants of the nucleic acid with 85-100% complementarity to SEQ ID NO:4 that result in impaired Trem2 R47H protein expression, such a misfolded protein leading to degradation, would be expected to yield a phenotype analogous to a Trem2 knockout mouse. Therefore, a skilled artisan would be unable to predict whether a species of nucleic acid sequence encompassed by claim 13 encodes for a Trem2 R47H protein that gives rise to the genetically modified mouse exhibiting one or more signs of non-familial late-onset Alzheimer’s disease as required by claim 1.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Eric B Wright whose telephone number is (571) 272-2607. The examiner can normally be reached Mo - Fr, 09:00 a.m. - 05:00 p.m. Eastern. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571) 272-4517.
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/Eric B Wright, PhD/Examiner, Art Unit 1632 /VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632