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. Pursuant to the amendment dated 24 Jun 2026, claims 5, 7, 12-13, and 16 are amended. Claims 5-7 and 12-24 are pending.
Restriction Requirement
A provisional election to group I, drawn to claims 5-7 and 12-16, without traverse was made in telephone conversation with Heather J. DiPietrantonio, PhD on 03 Mar 2026. As noted in the previous Office Action, affirmation of this election must be made by the Applicant. Affirmation of the election was not found in the response filed 24 Jun 2026. Claims 17-24 remain withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention. Claims 5-7 and 12-16 are considered on the merits.
Claim Objections
Objections to claims 5 and 16 are withdrawn due to amendments to the claims.
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.
Rejection of claims 5-7 and 12-16 is maintained 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. The grounds of rejection are maintained or adjusted as necessitated by amendments to the claims.
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 and the prior art do not provide sufficient teachings that would enable a skilled artisan to make and use the full scope of the claimed invention. The assessment step is generic with regard to whether or not a screened compound useful for the treatment of Alzheimer's disease. No treatment is available for Alzheimer's disease as of the earliest effective filing date of the present invention. Therefore, a skilled artisan would be unable to derive from the prior art how to perform the assessing step in claim 5 step (b). 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.
Response to Arguments
Applicant traverses the rejection on the basis that the principal issues regarding 1) the nexus between phenotype of the mouse model and Alzheimer's disease, 2) active steps for assessment, 3) examples demonstrating that a candidate compound reverses disease signs, and 4) predictability of Alzheimer's therapeutics are each enabled.
In response, Applicant's arguments have been fully considered but are not persuasive.
As noted previously, and as maintained, the basis for the rejection is that the assessment step is generic with regard to what comparisons are made and the criteria for success of a given candidate compound. Any deficiencies pointed to in the Wands factor analysis are used to illustrate why the claims, the specification, or the prior art do not provide sufficient detail or teachings for a skilled artisan to discern how to perform the assessment step and lack of predictability in identifying a compound for use in treating Alzheimer's disease, not to point out lack of enablement for other limitations.
Regarding phenotype of the mouse model, the Examiner agrees that addition of the structural definition of the mouse to the claim serves to clarify the phenotype. While the specification uses an open-ended definition of the phenotype, narrowing the claim scope to a specific embodiment enables a skilled artisan to further characterize signs of non-familial late-onset Alzheimer's disease in the recited mouse model in a predictable manner. The degree of phenotypic characterization is not in question, as the model need not be fully characterized for use in a screening method. Instead, due to lack of success in the art for developing an approved therapeutic for clinical use, it is unclear what aspects of the mouse model phenotype are relevant for screening a compound for use in the treatment of Alzheimer's disease. The claimed mouse model is, however, enabled for identification of a candidate compound when compared against a specific, appropriate control.
Regarding the assessment step, the Examiner disagrees that specifying 1) active steps for what comparisons are made or 2) what results would be indicative that a screened compound is a candidate compound are not required for enablement of a screening method. Compliance with the enablement is not a set standard, but is based the evidence from each of the Wands factors and what teachings are required for one skilled in the art to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993). Screening methods are developed for the express purpose of generating an output regarding candidate compounds - to continue development of the compound toward clinical use if success criteria are met, or to halt development of the compound if not. This particular result is required for a screening method. The ability of a skilled artisan to make the animal model, administer a compound, and to perform an assay related to one of the clinically relevant signs of the disease is not in question - those steps are enabled.
The assessment step is not merely an assay step, but is a mental process that requires comparison of the effect of the compound on the one or more signs of non-familial late-onset Alzheimer's disease against some type of control, such as a non-treated transgenic mouse carrying the modifications recited in claim 5 step (a) or a treated wild-type mouse, and at least one criterion for success for whether the compound is indicative of being a candidate compound for further development, such as the number of signs affected, which sign is affected, the degree to which the sign(s) is affected, or some other criterion not implicit in the claim.
With regard to therapeutic reversal, the Examiner agrees that therapeutic reversal is not required for enablement. The lacking of working example was pointed to because working examples can be relied upon as a factor in determining the enabled scope of the claims. Because no example of performing the screening method was provided, how the joint inventors regard the assessing step remains unclear.
The Examiner disagrees with the assertion that unpredictability of Alzheimer's therapeutics does not defeat enablement. The claim requires screening a compound for use in treating Alzheimer's disease. Therefore, as written, the claim requires predictability of the compound in a clinical setting, successful or not. Furthermore, the causes of prior clinical failures are not limited to the subtype of Alzheimer's disease. No treatment was available for any Alzheimer's disease subtype as of the earliest effective filing date of the claimed invention; therefore ascertaining how of a compound in an in vivo screening method might be assessed cannot be derived from the prior art. The ability of a skilled artisan to administer a compound and perform an assay is not in question. Assessment of the effect and correlation to use for treating Alzheimer's disease is in question. However, identification of a candidate compound for further development does not require predictability of success in a clinical setting, and identification can be made merely on the effect on clinically relevant symptoms in the recited transgenic mouse with respect to a specific control.
Rejection of claims 12-13 under 35 U.S.C. § 112(a) with regard to the written description requirement are withdrawn due to amendment to the claims.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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
/Eric B Wright/Examiner, Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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