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 .
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 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.
DETAILED ACTION
This action is in response to claim amendments filed 7/20/26. Claims 1-5, 10-11, and 13-16 are pending and under examination.
Withdrawn Rejections
The objection to the specification is withdrawn in light of the amendments.
The claim objections are withdrawn in light of the amendments.
The rejection under §112b is withdrawn in light of the amendments.
The rejection under §112a for “analogues” is withdrawn as claim 11 no longer recites this term.
Maintained Rejections and New Rejections Necessitated by Amendment
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 1-5, 10-11, and 13-16 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 reducing severity of symptoms/conditions associated with Alzheimer’s disease and delaying onset of AD, does not reasonably provide enablement for preventing AD. 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 claims recite “preventing or delaying the onset of” AD or any symptoms associated therewith. However, the art currently does not recognize any drug or method that results in the complete prevention of Alzheimer’s disease. See for example Reitz (IDS 11/29/23 citation C76) that states “as the currently available drugs only slightly affect disease severity and progression, AD remains at present effectively untreatable” (p.2 C1) and Stanford (IDS 11/29/23 citation C91) that states "unfortunately, there are no currently available FDA-approved medications proven to delay or slow progression of the underlying brain degeneration and loss of synaptic connections that occurs in Alzheimer’s disease”. Where the goal is recognized as difficult and as-yet unrealized, the evidence supporting a claim that such a result is achievable must necessarily be strong. The instant specification does not provide any working examples of AD prevention nor does it provide adequate guidance on how to overcome the art-recognized difficult nature of this goal. One skilled in the art could not practice the method of the claims to achieve the result of prevention of AD as claimed.
The specification uses genetic models of drosophila. The Aß drosophila demonstrate Aß accumulation and certain, specific symptoms. Complete genetic knockout of RBO is not equivalent to pharmaceutical inhibition of PI4KIIIα but is rather expected to show the greatest possible effect as the knockout equates to the protein not being expressed while a pharmaceutical inhibitor is not expected to be 100% effective. Even in this case, figure 1 demonstrates that while the rbo gene mutation ameliorates symptoms, it does not prevent those symptoms. Panel c demonstrates that the Aßarc and the two Aßarc/rbo models are similar after 16 days. After 26 days, while the Aßarc performs worse than the other two, they all appear worse than the control model, suggesting that symptoms were ameliorated, but onset was not delayed. The specification itself uses the term “ameliorates” in the various examples (paragraph 158 describing figure 19B; paragraph 157 describing figure 12; paragraph 153 describing figure 6; paragraph 115) but does not state that onset was delayed or prevented. Figure 8 demonstrates that tau and Aß models both perform worse than controls, which is not ameliorated by rbo; “rbo gene mutation could not ameliorate the lifespan shortening of flies over-expressing tau protein” (p.27), yet tau is a known AD-associated protein. Taken as a whole, the evidence observes specific aspects of AD, but not Alzheimer’s disease itself. Moreover, these results appear to be inconsistent with the conclusion that AD could be prevented or delayed.
MPEP §2164 notes that in vitro and in vivo models constitute a working example when that model correlates with the claimed method. Further, art recognized models—such as those in the instant specification—should be accepted as correlating unless there is evidence otherwise.
First, while flies and mice may be used as surrogate models for Alzheimer’s disease and recapitulate certain aspects of the disease, these subjects do not actually have Alzheimer’s disease. See e.g., Reardon (IDS 11/29/23 citation C74) teaching that AD does “not occur naturally in mice” (p.611 C2). Drummond (IDS 11/29/23 citation C27) describes APP/PS1 mice (the model instantly used; see remarks in parent application 15/570681 on 3/21/22 at p.9) but notes their deficiencies when it comes to recapitulating every aspect of AD (table 1; p.6) as well as being generally limited to modeling a very rare form of the disease (p.28).
The instant specification suggests that AD may exist in humans and dogs (paragraph 48); however, while other animals may suffer Alzheimer’s-like pathologies, “the complete behavioral and pathologic phenotype of Alzheimer’s disease…has not yet been identified in a nonhuman species” (Walker, abstract; IDS 11/29/23 citation C97). Thus, the claims are directed to achieving certain results in humans—and arguably dogs per the guidance in the specification—but treatment of flies and mice is not a working example of treating AD but rather a correlative model suggesting efficacy in treating AD. Thus, while the in vivo data provided in the specification may correlate to the disease, they are not examples of actual treatment of Alzheimer’s, while the claims are directed to preventing the disease.
The evidence supports a conclusion that the skilled artisan would not accept the instant models as reasonably correlating to the ability to prevent onset of Alzheimer’s disease in those at risk of Alzheimer’s disease, e.g., humans. The results in flies and mice are not indicative of the ability to prevent, reverse, or delay onset of AD in such subjects; there is not a single therapeutic which achieves any of these goals despite decades of attempts.
The art is replete with treatments that are promising in mice but then fail in humans. In addition to Reitz and Stanford, see for example Franco (IDS 11/29/23 citation C32), noting that there are many successful Alzheimer’s treatments in animal models but “none in humans” (title). Vitek (IDS 11/29/23 citation C96) teaches that animal models reflecting only a single aspect of AD fail because this does not mimic AD (abstract); the fly model used in the instant specification reflects only a single aspect of AD (Aßarc expression). Drummond (IDS 11/29/23 citation C27) describes APP/PS1 mice (the mouse model instantly used) but notes their deficiencies when it comes to recapitulating every aspect of AD (table 1; p.6) as well as being generally limited to modeling a very rare form of the disease (p.28). Drummond notes that “the response of endogenous mouse proteins to human PS1 is different from that in humans” and that “the downstream pathological effects” of these AD mouse models should be “interpreted carefully” because the animal responds differently than would a human (p.14). Reardon notes that drug companies have spent billions trying to prevent or even slow the progress of Alzheimer’s disease, but “to no avail” (p.611 C1), while those skilled in the art say “we appreciate that the models we had were insufficient” (p.611 C1). Reardon further teaches “many experimental drugs that have successfully removed [amyloid] plaques from mouse brains have not lessened the symptoms of Alzheimer’s disease in people. Such a method is also unpredictable in light of others who demonstrate that PAOs—the compounds of claim 5—may induce neurodegeneration rather than preventing it. Administering PAO, which is a PI4IIIα inhibitor—to a mouse—which is a “subject”—is within the scope of the instant claims, yet WO2004080416 (claim 10; IDS 11/29/23 citation B4) teaches this method causes neurodegeneration. While Applicant has demonstrated some degree of benefit in reducing symptoms in subjects which model Alzheimer’s disease, the specification does not demonstrate any evidence that would rise to the level of prevention or delayed onset, while the art provides ample evidence demonstrating that such a result is unpredictable and, so far, unachievable.
The claims encompass preventing onset of AD in any “subject”, while others have tried and failed to accomplish this goal. Taking the evidence as a whole, the results in the instant fly and mouse models are not reasonably correlated to the outcomes currently claimed, demonstrating that models of AD, particularly single aspect models such as Aß transgenics, do not correlate to the prevention or delay of AD. One skilled in the art could not practice the method of the claims to achieve the result of preventing onset of AD as claimed without undue experimentation.
Therefore, claims 1-5, 10-11, and 13-16 are not enabled for their full scope.
Double Patenting
Claims 1-5 and 13-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 11766420. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Under the BRI of instant claim 1, the instant claims include preventing/delaying symptoms associated with the onset of AD in a subject, i.e., the subject has AD. Reference claim 1 is directed to ameliorating AD symptoms by administering the same therapeutics as instant claims 1-5; see reference claims 1-5. Instant claims 13-16 describe downstream results or properties of the claimed therapeutics. Since the reference claims administering the same therapeutics, they must have the same properties. Chemical compounds and their properties are inseparable (In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA1963)), as are their processes and yields (In re Von Schickh, 362 F.2d 821, 150 USPQ 300 (CCPA 1966)).
Claims 10-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 11766420 in view of US20140357648 (‘648; previously cited) and CN103529182 (IDS11/29/23 citation B2).
US11766420 is discussed above as applied to instant claims 1-5 and 13-16, incorporated herein.
Regarding claim 11, ‘648 teaches administering acamprosate to treat AD (claims 1 and 3). Combining two known therapeutics to treat the same disease is prima facie obvious; “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See MPEP § 2144.06(I).
Similarly, regarding claim 10, ‘182 teaches inhibitors of RBO/EFR3a/EFR3b for treatment of AD (claim 8) and would be obvious to combine for the same reasons.
Response to Arguments
Applicant's arguments filed 7/20/26 have been fully considered but they are not persuasive.
Regarding the double patenting rejection, Applicant argues the reference patents would not make obvious the prevention of AD. This is not persuasive because the instant claims are not limited to preventing AD. The instant claims clearly encompass preventing or delaying symptoms associated with the onset of AD, which indicates the subject includes those with AD. Administering the same drug to the same population for treatment of the disease/symptoms would necessarily delay/prevent other symptoms associated with AD because the properties of the drug are inseparable from the compound. Further, other than Applicant’s assertion that a treatment does not make obvious prevention Applicant does not provide any evidence in support of this. Applicant is reminded that “arguments of counsel cannot take the place of factually supported objective evidence" (MPEP§2415).
Regarding enablement:
P.4-p. 5 second paragraph: Applicant argues the animal models are not a complete knockout and the intervention occurs at the beginning of the animal’s life. The second paragraph on page 5 concludes “can delay the onset of AD”. While the arguments for delaying onset are persuasive, this does not support prevention.
P.5 third paragraph-p.6 first paragraph: Applicant argues the transgenic flies were indistinguishable from control. However, the rejection sets forth why the animal models are not supportive of preventing AD.
P.6-p.7 first full paragraph: Applicant clarifies the results of the animal models. These animals are models of AD but do not have AD and are not indicative of the ability to prevent AD in humans and possibly dogs, which are the subjects that suffer AD.
P.7 second paragraph: Applicant argues that preventing does not mean completely eliminating the occurrence but should be interpreted as delaying onset or reducing severity of conditions at the time of onset. This is not persuasive. There is no special definition of “preventing” in the specification. Further, delaying onset and reducing severity of conditions are explicitly recited in the claim as alternatives to prevention. The onset of a disease is a binary: the disease onset either has or has not occurred. Therefore, prevention must mean the complete prevention of the disease from occurring as any other definition would fall within one of the other alternatives.
P. 8: Applicant argues the transgenic mouse model is widely accepted. This is not persuasive because the rejection articulates why there is sufficient cause to doubt the correlation of the model to the disease. Applicant argues that the FDA does not require perfect recapitulation and if this were adopted then all patents would face validity challenges. This is not persuasive because the FDA is not the regulatory agency for patents and so what the FDA does or does not require for approval is not relevant to the current inquiry. Further, a drug can be approved for use to treat AD without the FDA confirming that the drug wholly prevents the onset of AD. This is also indicated in the rejection of record in that, while Applicant is correct that certain drugs have been approved, not a single known drug has been demonstrated to prevent the onset of AD. Applicant also argues the drosophila model is useful for bridging the gap between basic research and translational medicine. This is not persuasive because this does not point to any reason to expect any results in drosophila to translate to the prevention of AD onset in humans.
P. 9: Applicant argues the reasonable correlation between the model and the claimed effect should be sufficient to support enablement. This contradicts MPEP §2164.02(II) that states “if the art is such that a particular model is recognized as correlating to a specific condition, then it should be accepted as correlating unless the examiner has evidence that the model does not correlate.” The Examiner has provided evidence that the model does not correlate to preventing AD and so the “reasonable correlation” of the animal models is not sufficient. Applicant argues the Examiner’s insistence that no drug can prevent AD should be ignored because this does not encourage innovation and all prophylactic methods would be rejected. This is not persuasive. Applications are determined on their own merits and what may or may not occur in a hypothetical application is of no relevance to the instant rejection. Further, the Examiner’s evidence that no drug has ever prevented AD is not provided to claim that prevention is impossible, but as objective evidence that Applicant’s results in animal models are not correlated to prevention of the disease itself (e.g., in humans), which is the proper analysis as set forth in the MPEP.
Taken together, Applicant does not provide any objective evidence of preventing AD onset. The animal models—while useful—do not correlate to preventing AD onset. The fact that others have used the same models and failed to prevent AD is evidence that the models do not provide the skilled artisan a reasonable expectation of achieving these claimed results. Applicant’s argument that the target is new and so the prior art cannot be used to negate the assertion of prevention is not persuasive because the ample evidence that others have not prevented AD properly shifts the burden to Applicant to provide objective evidence that, for this new target, the inhibition achieves a previously unobtainable result. Applicant has not met that burden for the reasons above.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 ADAM M WEIDNER whose telephone number is (571)272-3045. The examiner can normally be reached M-T 9-18; W-R 9-15.
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/Adam Weidner/ Primary Examiner, Art Unit 1675
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