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 .
Response to Amendment
The amendments received 11/17/2025 have been entered. Claims 16-21 and 23-29 are pending. Any objection or rejection set forth in the Office Action mailed 07/14/2025 not maintained herein has been overcome and is withdrawn. Any new grounds of rejection set forth herein is necessitated by amendment.
Examiner has considered Applicant’s arguments, in light of the claim amendments, regarding the outstanding rejections of claims 16-21, 23-26, and 29 under 35 U.S.C. 103 and finds them persuasive. The rejections are withdrawn.
Examiner acknowledges Applicant’s submission of English translations of foreign priority documents EP19315064.6 filed 07/09/2019 and EP19201179.9 filed 10/02/2019. The 102(a)(1) rejection of claims 26 and 29 over Bamia (Universite de Bretagne Occidentale; 2019) is withdrawn as Bamia is no longer prior art under 102(a)(1).
Election/Restrictions
Examiner has expanded the search to encompass the full scope of the claims. Claim 19 is no longer withdrawn and is rejoined herein. The Election of Species requirement set forth on 03/31/2025 is withdrawn.
Claim Objections
Claim 16 is objected to because of the following informalities: “reducing the amount of” should read “reduces the amount of”; "control of the progression of said proteinopathy" should read "controls the progression of said proteinopathy". Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 16-21 and 23-29 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.
Claim 16 recites “reducing the amount of misfolded proteins… at a relatively constant level”. The term “relatively constant level” does not convey any particular amount or degree and is therefore unclear. Claims 17-21 and 23-25 do not clarify the limitation at issue and are also rejected.
Claim 16 recites “the maintains the amount of”. There is insufficient antecedent basis for this limitation.
Claims 16-21 and 23-29 directly or indirectly recite “isomers… thereof”. The term “isomers” renders the claims indefinite as isomers also includes constitutional isomers, i.e., isomers with the same type and number of atoms but in a different configuration. It is unclear which isomers are within the scope of the claims, nor can it be ascertained whether every constitutional isomer would have the same properties as the claimed compounds. Correction is required.
Claim Rejections - 35 USC § 112(a)
Claims 16-21 and 23-29 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 reduction of symptoms caused by a proteinopathy selected from the group consisting of Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, kuru, VPSPr disease, Lewy body disease, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, frontotemporal dementia, type 2 diabetes, oculopharyngeal muscular dystrophy, bovine spongiform encephalopathy, scrapie, chronic wasting disease of cervids, feline spongiform encephalopathy, camel spongiform encephalopathy and exotic ungulate encephalopathy, does not reasonably provide enablement for prevention or prophylaxis. 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.
As stated in the MPEP 2164.01 (a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.”
In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described. They are:
1. the nature of the invention,
2. the state of the prior art,
3. the predictability or lack thereof in the art,
4. the amount of direction or guidance present,
5. the presence or absence of working examples,
6. the breadth of the claims,
7. the quantity of experimentation needed, and
8. the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The term “treatment” is defined on page 9 of the specification and said definition also embraces prevention and prophylaxis (lines 8-9).
It is presumed “prevention” of the claimed disease would require a method of identifying those individuals who will develop the claimed diseases before they exhibit symptoms. There is no evidence of record that would guide the skilled clinician to identify those who have the potential of becoming afflicted.
The factors to be considered in making an enablement rejection were summarized above. 1) As discussed above, preventing diseases requires identifying those patients who will acquire the disease before the proteinopathy occurs. This would require extensive and potentially opened ended clinical research on healthy subjects. 2) The third paragraph on page 9 defines treatment as including prevention and prophylaxis. 3) There is no working example of such a preventive procedure in man or animal in the specification. 4) The claims rejected are drawn to clinical pharmacology and are therefore physiological in nature. 5) The state of the art is that no general procedure is art-recognized for determining which patients generally will suffer from proteinopathies before the fact. 6) The artisan using Applicants invention would have a PhD or would be a Board-Certified physician with an MD degree. Despite intensive efforts, pharmaceutical science has been unable to find a way of getting a compound to be effective for the prevention of proteinopathies. Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished, In re Ferens, 163 USPQ 609. No such evidence has been presented in this case. The failure of skilled scientists to achieve a goal is substantial evidence that achieving such a goal is beyond the skill of practitioners in that art, Genentech vs. Novo Nordisk, 42 USPQ2nd 1001, 1006. This establishes that it is not reasonable to any agent to be able to prevent a proteinopathy. That is, the skill is so low that no compound effective generally against the prevention of proteinopathies. 7) It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved" and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
Claim Rejections - 35 USC § 103
Claim(s) 27-28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hatakeyama et al. (2008; IDS filed 01/07/2022)as applied to claims 16, 18, and 22 above, and further in view of Sarkar et al. (Cell Death and Differentiation; 2009), Nguyen (Universite de Bretagne Occidentale - Brest; 2013), and Lorenzen (Humboldt-Universität zu Berlin; 2006). All references have been previously cited.
Hatakeyama et al. discloses a method of treating dementia patients with Alzheimer’s disease comprising administering to the patients azelastine hydrochloride (p. 59) which resulted in improved psychological symptoms (p. 59, col. 1 – p. 60).
Hatakeyama et al. does not teach combining azelastine with another compound. These limitations are obvious over Sarkar et al., Nguyen, and Lorenzen.
Lorenzen discloses a compound screening for inhibitors of PRPSc formation (misfolded prion protein) comprising administering compounds to ScN2a cells, which identified ebastine as a PRPSc formation inhibitor and lead structure (p. 24-25, p. 29 Table 2.1, Figure 2.41). Lorenzen additionally discloses that Creutzfeldt-Jakob disease (prion disease) and Alzheimer’s disease (amyloidosis) are well-known protein misfolding diseases wherein misfolded proteins are deposited (p. 21).
Sarkar et al. discloses that loperamide upregulates autophagy and enhances clearance of aggregate proteins in neurodegenerative diseases (p. 48, Table 1; p. 51 col. 2 – p. 52 col. 1). Sarkar et al. additionally discloses that protein aggregation is a feature of several neurodegenerative disorders, such as Alzheimer’s disease and prion diseases, and that autophagy aids in clearing aggregate-prone proteins (p. 47).
Nguyen teaches that flunarizine has activity against yeast and mammalian PRPSc formation (p. 135). Nguyen additionally discloses that flunarizine inhibits PFAR (p. 137-138) and that its antiprion activity is linked to its activity as an antihistamine (H1 receptor antagonist) (p. 139-140).
It would have been prima facie obvious to combine azelastine with loperamide, ebastine, or flunarizine. One would have been motivated to do so, with reasonable expectation of success, as the aforementioned compounds have properties that would be expected to enhance the effects of azelastine by reducing protein aggregates and have been suggested for treating protein misfolding disorders such as Alzheimer’s disease.
Response to Arguments
Applicant's arguments filed 11/17/2025 have been fully considered but they are not persuasive.
35 U.S.C. 112(b)
Regarding the rejection under 35 U.S.C. 112(b) over the term “isomers”, Applicant argues that the definition of “isomer” as in the specification states that while conformational isomers are included, “In the context of the present invention, it is understood that the isomer of a compound retains all or some of the function of said compound (here the inhibition of PFAR)” (pages 7-8 of Remarks). However, this is not persuasive. An isomer that retains “all or some of the function” of a compound does not convey the degree to which the function is retained, nor does it allow one of ordinary skill in the art to envisage what structures would maintain even a modicum of the function of the parent compound. Moreover, a compound may have multiple functions, and the statement “here the inhibition of PFAR” does not make clear that the scope of the claims is only limited to those retaining the function of inhibiting PFAR. The language may be more broadly interpreted as exemplary, which suggests that other functions are possible. The rejection is maintained.
35 U.S.C. 112(a)
Applicant has amended the scope of claim 16 and argues, on page 8 of Remarks, “it is believed that the amendments made to the claims have rendered this issue moot.” This is not persuasive. The amendments to claim 16 further defines what the treatment does (“delays or reduces symptoms… reducing the amount of misfolded proteins…”) but does not necessarily nor clearly exclude prevention and/or prophylaxis from the scope of the claims, which still recite “A method of treating”. The rejection is maintained.
35 U.S.C. 103
Regarding the rejection of claims 27 and 28 under 35 U.S.C. 103, Applicant argues that the combination of flunarizine with ebastine produces an unexpected advantage, wherein flunarizine and ebastine exhibit a synergistic effect and that the Examiner relies on hindsight reasoning (p. 10-12 of Remarks). This is not persuasive.
First, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Second, while Applicant argues that the synergy of ebastine in combination with flunarizine is unexpected, the scope of the claims is markedly broader than that of the results pointed to by Applicant. Per MPEP 716.02(d), unexpected results must be commensurate in scope with the claimed invention. The claims are directed toward a compositions comprising at least two different compounds, being “at least one compound selected from ebastine, azelastine, duloxetine, atomoxetine, benzydamine, biperiden, chloropyramine, citalopram, dicyclomine, nefopam, orphenadrine, prenylamine, triflupromazine and zimelidine,” and “at least one different compound selected from flunarizine, loperamide, ebastine, azelastine, metixene, guanabenz, 6-aminophenanthridine, imiquimod, tacrolimus, astemizole, doxycycline, amitriptyline, atomoxetine, benzydamine, biperiden, chloropyramine, chlorpromazine, citalopram, clemastine, clomipramine, desipramine, desloratadine, dicyclomine, diphenhydramine, doxepin, duloxetine, fluoxetine, haloperidol, imipramine, nefopam, orphenadrine, prenylamine, quinacrine (mepacrine), reboxetine, thioridazine, trifluoperazine, triflupromazine, alimemazine (trimeprazine) and zimelidine.” The working examples, however, only demonstrate synergy when flunarizine is combined with azelastine, ebastine, or loperamide. Moreover, the scope of the claims includes any concentration of the aforementioned compounds, not just those that are synergistic. The compounds of the instant claims additionally differ greatly in their function, ranging from antihistamines to SSRIs. One would not be able to extrapolate from the tested combinations that flunarizine and fluoxetine, for example, would be synergistic in combination.
Regarding Applicant’s arguments against Hatakeyama et al., Sarkar et al., Nguyen, and Lorenzen (Remarks pages 11-12), Examiner notes that claims 27 and 28 do not require that the combined compounds inhibit PFAR or treat a proteinopathy. Nevertheless, while Applicant argues that none of the references suggest treatment of a proteinopathy, this argument is not persuasive. The definition of “treatment” as in the instant specification (p. 9) includes reduction of symptoms caused by a protein misfolding disease, which does not necessarily require specifically treating protein misfolding, inhibiting PFAR, or reducing protein aggregation. Thus, since Hatakeyama et al. discloses the use of azelastine for treating a condition and/or symptom associated with a proteinopathy, one of ordinary skill in the art would be apprised that azelastine would be beneficial for treating dementia and/or Alzheimer’s. Sarkar et al., Nguyen, and Lorenzen additionally suggest that loperamide, fludrazine, and ebastine, respectively, would be beneficial for treating Alzheimer’s. MPEP 2144.06, "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). One of ordinary skill in the art would recognize that the claimed compounds would be beneficial in combination, which flows logically from their common utility.
For these reasons, the rejection is maintained.
Conclusion
No claims are allowed.
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 MADELINE E BRAUN whose telephone number is (703)756-4533. The examiner can normally be reached M-F 8:30am-5:00pm ET.
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/M.E.B./Examiner, Art Unit 1624 01/15/2026
/BRENDA L COLEMAN/Primary Examiner, Art Unit 1624
1 Examiner notes that the structures depicted in Figure 2.4 for ebastine and ethacridine appear to be switched.