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 .
Priority
This application was filed 8/10/2023 and is a 371 of PCT/US2022/015917 (02/10/2022) which has a provisional 63/149124 (01/12/2021). Claims 1-4, 6, 14, 18, 21-22, 28-31, 34, 39, 43, 45-46 and 50-52 are before the Examiner.
Claim Rejections - 35 USC § 112
Claims 31, 34, 39, 43, 45-46, 50 and 52 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains 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. Applicants are not enabled for preventing any TTR aggregate formation or formation of high molecular weight aggregates. The only established prophylactics are vaccines not the compounds such as presently claimed. In addition, it is presumed that “prevention” of the claimed diseases would require a method of identifying those individuals who will develop the claimed diseases before they exhibit the 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] have been summarized as a) the quantity of experimentation necessary, b) the amount of direction or guidance presented, c) the presence or absence of working examples, d) the nature of the invention, e) the state of the prior art, f) the relative skill of those in that art, g) the predictability or unpredictability of the art, h) and the breadth of the claims”, In re Rainer, 146 USPQ 218 (1965); In re Colianni, 195 USPQ 150, Ex parte Formal, 230 USPQ 546. a) As discussed above, preventing diseases required identifying those patients who will acquire the disease before the disease occurs. This would require extensive and potentially open-ended clinical research on healthy subjects. B) The passage spanning the first few pages of the specification teaches that the prevention of complex formation is thought to hold promise for the halt or progression of dry age-related macular degeneration (AMD) among other diseases. C) There are no working examples of such preventive procedure in a man or animal in the specification. D) The claims rejected are drawn to the medical prevention and are therefore physiological in nature. E) The state of the art is that no general procedure is art-recognized for determining which patients generally will become afflicted with disease before the fact. F) The artisan using Applicant’s invention would be a board certified physician who specializes in treating diseases. Despite intensive efforts, pharmaceutical science has been unable to find a way of getting a compound to be effective for the prevention of diseases generally. 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 the practitioners in that art, Genetech vs. Novo Nordisk, 42 USPQ2nd 1001, 1006. This establishes that it is not reasonable to any agent to be able to prevent diseases generally. That is, the skill is so low that no compound effective generally against diseases has ever been found let alone one that can prevent such conditions. G) 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, 214 (CCPA 1970). H) The claims broadly read on all patients, not just those undergoing therapy for the claimed diseases and on the multitude of compounds embraced by formula (I).
The Examiner suggests deletion of the word “prevention”.
Claims 31, 34, 39, 43, 45-46, 50 and 52 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 stabilizing TTR tetramers, does not reasonably provide enablement for treating TTR amyloidosis disease, treating a disease characterized by excessive lipofuscin or treating a disease characterized by a TTR amyloidosis disease or by excessive lipofuscin accumulation in the retina or both a TTR amyloidosis disease and a disease characterized by excessive lipofuscin. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
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”. These factors include 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, 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) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The nature of the invention: The nature of the invention is the method of treating a disorder that is modulated by TTR.
The state of the prior art: The state of the prior art is that it involves screening in vitro and in vivo to determine which compounds exhibit the desired pharmacological activities (i.e. what compounds can treat which specific disease). There is no absolute predictability even in view of the seemingly high level of skill in the art. The existence of these obstacles establishes that the contemporary knowledge in the art would prevent one of ordinary skill in the art from accepting any therapeutic regimen on its face.
The predictability in the art: It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F. 2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the instantly claimed invention is highly unpredictable since one skilled in the art would recognize that in regards to the therapeutic effects of all diseases, whether or not the modulation of TTR would make a difference in the disease. Hence, in the absence of a showing of a nexus between any and all known diseases and the modulation TTR, one of ordinary skill in the art is unable to fully predict possible results from the administration of the compound of claim 1 due to the unpredictability of the role of modulation of TTR. Those of skill in the art recognize that in vitro assays and or cell-cultured based assays are generally useful to observe basic physiological and cellular phenomenon such as screening the effects of potential drugs. Garai and Li both teach that TTR activity is important and might be useful to treat diseases in the future.
The presence or absence of working examples: The compounds of the instant invention have been shown to work in vitro and in vivo for the TTR activity. However, there are no working examples of the instant compounds treating a specific disease.
The amount of direction or guidance present: The guidance present in the specification is that of the compounds have TTR activity. But applicant teaches that this activity might have use to treat diseases. This is stated in the last paragraph in the instant specification. The instant compounds are a novel class of TTR tetramer kinetic stabilizers that show promise. The specification does not seem to enable a correlation between the mediation of TTR and the treatment of all the diseases linked to TTR activity.
The breadth of the claims: The claims are drawn to the treatment of many diseases mediated by TTR with the compound of claim 1.
The quantity of experimentation needed: The quantity of experimentation needed is undue. One skilled in the art would need to determine what disease out of all diseases known to be linked to TTR would be benefited by the mediation of TTR and then would further need to determine which of the claimed compounds would provide treatment of the disease.
The level of the skill in the art: The level of skill in the art is high. However, due to the unpredictability in the pharmaceutical art, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro and in vivo screening to determine which compounds exhibit the desired pharmacological activity and which diseases would benefit from this activity.
Thus, the specification fails to provide sufficient support of the broad use of the compounds of claim 1 for the treatment of “disease”. As a result necessitating one of ordinary skill to perform an exhaustive search for which diseases can be treated by which compound of claim 1 in order to practice the claimed invention.
Genentech Inc. v. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”.
Therefore, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, one of ordinary skill in the art would have to engage in undue experimentation to test which diseases can be treated by the compounds of the instant claims, with no assurance of success.
This rejection can be overcome by limiting the claims to the stabilizing TTR tetramers in a mammal (the first listed treatment in claim 31).
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 31, 34, 39, 43, 45-46, 50 and 52 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. Specifically, it is unclear as to what is being claimed due to the excessive use of “or” in the claims. Clarification is required.
Claim Rejections - 35 USC § 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.
Claims 1-2 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US Pat 9994537 Cisar Cisar teaches compounds such as #96 on col 188
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as pharmaceuticals that anticipate the instant claims.
Claims 1-4, 6, 14, 18, 21-22, 28-31, 34, 39, 43, 45, 46, 50 and 52 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cioffi. Cioffi teaches many compounds as shown by the formula of page 12
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and continuing on pages 14, 18, 19, 20 and Table 1 on page 29 as pharmaceuticals that anticipate the instant claims. These compounds are associated with TTR aggregation and TTR tetramer binding potency. These anticipate the instant claims.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to D MARGARET M SEAMAN whose telephone number is (571)272-0694. The examiner can normally be reached M-F 8am-4pm Eastern.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at 571-272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/D MARGARET M SEAMAN/Primary Examiner, Art Unit 1625