DETAILED ACTION
Claims 1, 4-8, 10-14, 16, 18-20, 22-24, 27 and 29 are currently pending in the instant application.
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
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Information Disclosure Statement
Applicant's Information Disclosure Statements filed on 11/28/2023 and 05/31/2024 have been considered. Please refer to Applicant's copies of the 1449 submitted herewith.
Claim Objections
Claim 5 is not in proper Markush format. See MPEP 2173.05 (h) which states that Markush type claim recites alternatives in a format such as “selected from the group consisting of A, B and C.” See Ex parte Markush, 1925 C.D. 126 (Comm’r Pat. 1925), MPEP 803.02. The claims do not contain the phrase “or” between the final two species, or recite “selected from the group” in the preamble of the claim or have commas between the species. Appropriate correction is required.
Claim 24 does not have an “or” between the alternatives for Ring A. For example, in the 8th line of the claim, there should be an “or” before “optionally 1, 2, or 3 substituents selected form: halo” to signify that the following phrase is an additional option. Similarly, there should be an “or” before the “optionally wherein Ring A is”.
Claim Rejections - 35 USC § 112
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.
Claim 29 is 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 treating a condition associated with inhibitors of Factor XIIa, does not reasonably provide enablement for preventing any condition or treating disease beyond thrombosis or thromboembolic disorders associated with inhibitors of Factor XIIa. 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/use the invention commensurate in scope with these claims. The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988).
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 need 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.
The nature of the invention
In the instant case, the nature of the invention for a method of preventing or treating a condition selected from thrombosis, deep venous thrombosis, etc.
The state of the prior art and the predictability or lack thereof in the art
The state of the prior art is that the pharmacological art involves screening invitro and in vivo to determine which compounds exhibit the desired pharmacological activities (i.e. what compounds can prevent any conditions). 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 that contemporary knowledge in the art would prevent one of ordinary skill in the art from accepting any preventive regimen on its fact.
The instant claimed invention is highly unpredictable as discussed below:
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427F.2d833, 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. The burden of enabling one skilled in the art to prevent a condition would be much greater than that of enabling the treating of a condition. In the instant case, the specification does not provide guidance as to how one skilled in the art would accomplish the objective of preventing any condition. Nor is there any guidance provided as to a specific protocol to be utilized in order to show the efficacy of the presently claimed active ingredients for preventing any condition.
"To prevent" actually means to anticipate or counter in advance, to keep from happening etc. (as per Webster's II Dictionary) and there is no disclosure as to how one skilled in the art can reasonably establish the basis and the type of subject to which the instant compositions can be administered to order to have the "prevention" effect. There is no evidence of record, which would enable the skilled artisan in the identification of the people who have the potential of becoming afflicted with any condition. Since applicants "preventive" assertion is contrary to what is known in medicine, proof must be provided that this revolutionary assertion has merits.
According to prior art such as WO 2019/186164, cited in IDS filed 11/28/2023, inhibitors of Factor Xlla may be useful as anticoagulants. Factor XII (FXI I) was identified as a coagulation protein in the intrinsic pathway of blood coagulation as FXII deficient patients had marked prolongation of the in vitro surface-activated coagulation time. However, series of investigations have convincingly shown that FXI I has no role in normal haemostasis.
The amount of direction or guidance present and the presence or absence
of working examples
The specification does not provide examples of prevention of disease. It discusses several assays that can be used to test the biological activity of the compounds in screening of activity of FXIIa and other proteases (see p. 233). Further selectivity for thrombin and FXa showing preferential inhibition of FXIIa over FXa and thrombin of the compounds is tested (see p. 234).
The breadth of the claims
The instant breadth of the rejected claims is broader than the disclosure, specifically, the instant claims are drawn to method of preventing or treating a condition selected from thrombosis, deep venous thrombosis, etc (see claim 29). However the specification only provides evidence that the compounds inhibit Factor XIIa, and thus only conditions associated with inhibition of Factor XIIa would be treated.
The quantity or experimentation needed and the level of skill in the art
It would require undue experimentation of one of ordinary skill in the art to ascertain the effectiveness of the compound in preventing or treating various conditions. Factors such as "sufficient working examples", "the level of skill in the art" and "predictability", etc. have been demonstrated to be sufficiently lacking in the instant case for the instant method claims. Therefore, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, it is apparent that undue experimentation is necessary because of variability in prediction of outcome that is not addressed by the present application disclosure, examples, teaching and guidance presented. Absent factual data to the contrary, the amount and level of experimentation needed is undue.
Claim Rejections - 35 USC § 112
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 24 and 29 is 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.
Regarding claim 24, the phrase "optionally" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 29, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). There are several instances of the phrase such as found throughout the claim.
Further claim 29 recites phrases in parenthesis such as (including unstable angina); (pulmonary vein isolation, VT ablation); (including left-sided ablation…) and (unless complex anatomical setting), which renders the claim unclear since it is unclear if the limitations in the parenthesis are required. Note: these are examples of phrases in parenthesis in the claim and may not be every instance of phrases in parenthesis found in the claim.
Regarding claim 29, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claim 29 recites “e.g. congenital heart disease”.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 14 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 14 recites that the residue is
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. However claim 14 depends on claim 1, which only recites that the residue can be
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. Thus claim 14 is broader in scope than claim 1, the claim upon which it depends. Applicant may cancel claim 14, amend the claim to place it in proper dependent form, rewrite claim 14 in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 4-6, 11-13, 16, 18-20, 22-24, 27 and 29 are rejected under 35 U.S.C. 103 as being obvious over Philippou (see WIPO Pub No. 2019/186164, pub. 10/03/2019, cited in IDS filed 11/28/2023).
Philippou teaches compounds of formula (I)
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and exemplifies compounds such as
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(see p. 49),
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and
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(see p. 50). The compounds are taught in a formulation with an excipient (see p. 52, paragraph [00111]) and in prevention or treatment of conditions, including thrombosis, etc (see p. 53, paragraph [00115]).
These exemplary compounds correspond to a compound of Formula (I) wherein X is C(O); R1 is substituted or unsubstituted 3 to 8 membered monocyclic heterocyclic group comprising a N connected to -X- via a nitrogen atom; R2 is H; m is 0; L is a bond; R4a is H; R4e and R4f are H, n is 1 and R4 is aryl substituted with R4i, or one of R4e or R4f is H and the other is 6 to 10 membered aryl substituted with R4i, n is 1, and R4 is H; R5 is H; R5a and R5b are H; o is 1 and Ring A is substituted or unsubstituted 6 to 10 membered bicyclic aryl group.
Rather than having the X-R1 substituent located para to the C(O)-pyrroline ring on the piperidine ring as found in the instant claims, the X-R1 substituent is located meta to the C(O)-pyrroline ring on the piperidine ring. According to MPEP 2144.09, Section II, compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious).
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Note also In re Deuel 34 USPQ2d 1210, 1214 which states, “Structural relationships may provide the requisite motivation or suggestion to modify known compounds to obtain new compounds. For example, a prior art compound may suggest its homologs because homologs often have similar properties and therefore chemists of ordinary skill would ordinarily contemplate making them to try to obtain compounds with improved properties.”
In the absence of unexpected results, one skilled in the art would expect that the instant claims which are directed to compounds that are positional isomers to the compounds of Philippou to be prima facie. One skilled in the art would be motivated to synthesize structurally similar compounds with the expectation that they would have similar properties and utilities. The explicit teaching of Philippou with the enabled examples would have motivated one skilled in the art to synthesize compounds with such generic teaching with the expectation that they would have similar utility as inhibitors of Factor XIIa.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 4-6, 11-13, 16, 18-20, 22-24, 27 and 29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,336,991 (hereafter referred to as ‘991). Although the claims at issue are not identical, they are not patentably distinct from each other because ‘991 is drawn to compounds of formula
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including exemplified compounds
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(see col. 458) as well as other compounds in col. 459 of claim 18, and compositions comprising said compounds. The compounds taught by ‘991 correspond to a compounds of Formula (I) wherein X is C(O); R1 is substituted or unsubstituted 3 to 8 membered monocyclic heterocyclic group comprising a N connected to -X- via a nitrogen atom; R2 is H; m is 0; L is a bond; R4a is H; R4e and R4f are H, n is 1 and R4 is aryl substituted with R4i, or one of R4e or R4f is H and the other is 6 to 10 membered aryl substituted with R4i, n is 1, and R4 is H; R5 is H; R5a and R5b are H; o is 1 and Ring A is substituted or unsubstituted 6 to 10 membered bicyclic aryl group.
Rather than having the X-R1 substituent located para to the C(O)-pyrroline ring on the piperidine ring as found in the instant claims, the X-R1 substituent is located meta to the C(O)-pyrroline ring on the piperidine ring. According to MPEP 2144.09, Section II, compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious).
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Note also In re Deuel 34 USPQ2d 1210, 1214 which states, “Structural relationships may provide the requisite motivation or suggestion to modify known compounds to obtain new compounds. For example, a prior art compound may suggest its homologs because homologs often have similar properties and therefore chemists of ordinary skill would ordinarily contemplate making them to try to obtain compounds with improved properties.”
In the absence of unexpected results, one skilled in the art would expect that the instant claims which are directed to compounds that are positional isomers to the compounds of ‘991 to be prima facie. One skilled in the art would be motivated to synthesize structurally similar compounds with the expectation that they would have similar properties and utilities.
Allowable Subject Matter
Claims 7-8, 10 and 14 would be allowable over the prior art of record once the 112 and any objections were overcome.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAREN CHENG whose telephone number is (703)756-4699. The examiner can normally be reached M-F, 9AM-6PM PST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam Milligan can be reached at 571-270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KAREN CHENG/Primary Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623