DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-3, 6, 26-29, 36-39, 42-45, 101-136 are pending. Claims 4, 5, 7-25, 30-35, 40, 41, and 46-100 are cancelled.
Status of Priority
The present application is claiming the benefit of U.S. Provisional Application No. 63/375,647, filed September 14, 2022.
Information Disclosure Statement
The information disclosure statement filed on February 9, 2024 cites the following non-patent literature:
BARDIA A, et al., “Functional polymorphisms in XRCC-1 and APE-1 contribute to increased apoptosis and risk of ulcerative colitis” Inflamm Res, 2012, 61(4):359-365.
Examiner notes that Applicant only provided a page that includes the citation of this reference but does not provide the reference itself. Hence, the Bardia NPL reference was not considered. All remaining references cited in the IDS’s provided by Applicant are considered.
Specification - Disclosure
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claim 3 is objected to because of the following informalities:
“a peak 13.7 ± 0.2 degrees 2-theta” should read “a peak at 13.7 ± 0.2 degrees 2-theta”
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a) – Written description
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 44, 45, 111, 112, 123, 124, 135, and 136 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 44, 111, 123, and 135 are directed towards compositions of claims 36, 105, 117, and 129, respectively, wherein the composition comprises about 50 mg to about 600 mg of the Compound 1 calcium salt. In the instant specification, it mainly discloses compositions comprising Compound 1 calcium salt in an amount that is molar equivalent to an amount of free Compound 1.
There is a section in the instant specification that states:
“In some embodiments, the administering is orally administering a composition that is in an oral dosage, for example, a tablet or a capsule, form… In some embodiments, the effective amount of Compound 1 calcium salt is about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, about 240 mg, about 250 mg, about 300 mg, about 350 mg, about 360 mg, about 400 mg, about 420 mg, about 450 mg, about 480 mg, about 500 mg, about 540 mg, about 550 mg, about 600 mg, or about 650 mg per day” (para. 0217 and 0221).
However, these doses of Compound 1 calcium salt in a composition comprising Compound 1 calcium salt are discrete doses and are not a continuous range of doses as recited in the claims (i.e., about 50 mg to about 600 mg).
Hence, claims 44, 111, 123, and 135 are rejected for failing to comply with the written description requirement.
Claims 45, 112, 124, and 136, which are dependent on claims 44, 111, 123, and 135, respectively, are also rejected for further requiring and/or reciting the limitations of 44, 111, 123, and 135 which lack written description support.
Claim Rejections - 35 USC § 112(a) - Enablement
Claims 39, 108, 120, and 132 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.
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 evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these factors include:
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, and
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 nature of the invention
The nature of the invention claims Compound 1 (APX3330) salts and esters. The invention also provides compositions comprising a Compound 1 salt or ester. The invention also provides compounds of formula (I) and formula (II) and pharmaceutically acceptable salts thereof. The invention further provides compositions comprising a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or vehicle. The invention also provides methods for treating or preventing a disease, such as cancer, a liver disorder, an ocular disorder, a cardiovascular disorder, fibrosis, or an inflammatory disorder, comprising administering to a subject in need thereof an effective amount of a Compound 1 salt or ester; or compound of formula (I) or formula (II), or pharmaceutically acceptable salt thereof.
The level of the skill in the art
The level of ordinary skill in the art is relatively high. A person of ordinary skill would typically have formal training in medicinal chemistry would be familiar with standard methods for evaluating therapeutic efficacy of compounds.
State of the prior art
Prior art referenced:
Patel et al. (Patel) (Patel, P.B. et al. Ophthalmic Drug Delivery System: Challenges and Approaches. Systematic Reviews in Pharmacy. 2010, 1, 113-120.)
Patel teaches that development of an ophthalmic drug delivery device requires careful consideration of multiple formulation and device-related factors, including the anatomical site of administration within the eye (pg. 113, “Introduction” section, 1st paragraph), the required drug bioavailability, and the desired release kinetics (pg. 115, right col., “Approaches in ophthalmic drug delivery system” section, 1st paragraph) all of which influence the selection and design of the delivery device and the manner in which a drug substance may be incorporated or coated onto such a device.
The amount of direction or guidance present and quantity of experimentation necessary
Since the performance of an ophthalmic drug delivery device is highly dependent on the aforementioned device-related factors and because the specification provides no guidance on how the instant crystalline form of Compound 1 calcium salt could be incorporated into or coated onto such a device, a person of ordinary skill in the art would be require undue experimentation to determine suitable device materials, loading methods, and drug release profiles for the instant compound.
The presence or absence of working examples
The instant application discloses a composition which comprises a novel crystalline form of Compound 1 calcium salt characterized by specific XRPD peaks. However, the instant specification provides no information regarding physicochemical properties of this crystalline salt relevant to ophthalmic device-based drug delivery such as compatibility with device materials or drug release characteristics. While, the instant specification does provide the results from a safety and efficacy study of Compound 1 calcium salt in patients with an ocular disease (Example 7), this study investigated the safety and efficacy of orally administered Compound 1 calcium salt, not ophthalmically administered Compound 1 calcium salt via an ophthalmic drug delivery device.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
Claims 1, 2, 26-29, 36-39, 42-45, and 101-112 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:
A compound 1 calcium salt that exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 4.1 ± 0.2 degrees 2-theta, a peak at 5.3 ± 0.2 degrees 2-theta, a peak at 5.8 ± 0.2 degrees 2-theta, a peak at 6.3 ± 0.2 degrees 2-theta, a peak at 13.7 ± 0.2 degrees 2-theta, and a peak at 14.1 ± 0.2 degrees 2-theta (corresponds to instant claim 3)
does not reasonably provide enablement for:
A compound 1 calcium salt that exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 5.8 ± 0.2 degrees 2-theta and a peak at 6.3 ± 0.2 degrees 2-theta (corresponds to instant claim 1)
and
A compound 1 calcium salt that exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 5.8 ± 0.2 degrees 2-theta and a peak at 6.3 ± 0.2 degrees 2-theta, and further comprising a peak at 13.7 ± 0.2 degrees 2-theta or a peak at 14.1 ± 0.2 degrees 2-theta (corresponds to instant claim 2)
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 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 evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these factors include:
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, and
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 nature of the invention
See “1. The nature of the invention” subsection from the “Claim Rejections - 35 USC § 112(a) – Enablement” section discussed above.
The level of the skill in the art
See “2. The level of the skill in the art” subsection from the “Claim Rejections - 35 USC § 112(a) – Enablement” section discussed above.
State of the prior art
Prior art referenced:
Brittain (Brittain, H.G. Polymorphism in Pharmaceutical Solids, 2nd ed.; Drugs and the pharmaceutical sciences, 2009.)
A claimed crystalline polymorph is generally considered adequately described when characterized by at least five XRPD peaks (See Brittain, pg. 334, last paragraph, last sentence).
The presence or absence of working examples
The instant application discloses a procedure for preparing a calcium salt of Compound 1 that exhibits an XRPD pattern comprising a peak at 4.1 ± 0.2 degrees 2-theta, a peak at 5.3 ± 0.2 degrees 2-theta, a peak at 5.8 ± 0.2 degrees 2-theta, a peak at 6.3 ± 0.2 degrees 2-theta, a peak at 13.7 ± 0.2 degrees 2-theta and a peak at 14.1 ± 0.2 degrees 2-theta.
The specification does not disclose procedures or conditions for preparing other crystalline forms of the Compound 1 calcium salt that would exhibit an XRPD pattern comprising a peak at 5.8 ± 0.2 degrees 2-theta and a peak at 6.3 ± 0.2 degrees 2-theta, but differ in other aspects of their XRPD patterns.
The specification also does not disclose procedures or conditions for preparing other crystalline forms of the Compound 1 calcium salt that would exhibit an XRPD pattern comprising a peak at 5.8 ± 0.2 degrees 2-theta, a peak at 6.3 ± 0.2 degrees 2-theta, and a peak at 13.7 ± 0.2 degrees 2-theta or a peak at 14.1 ± 0.2 degrees 2-theta, but differ in other aspects of their XRPD patterns.
The amount of direction or guidance present and quantity of experimentation necessary
The specification does provide an additional procedure for the preparation of a second crystalline form of a Compound 1 calcium salt that exhibits an XRPD pattern different from that of the aforementioned Compound 1 calcium salt (i.e., XRPD pattern does not comprise a peak at 5.8 ± 0.2 degrees 2-theta and a peak at 6.3 ± 0.2 degrees 2-theta). Thus, the instant specification demonstrates that different crystalline forms of the same compound is highly dependent on variables such as solvent systems and temperature/pressure/drying conditions utilized.
Since the instant specification provides no guidance for obtaining the full range of crystalline forms encompassed by claims 1 and 2, a person of ordinary skill in the art would require undue experimentation to identify appropriate experimental conditions for the synthesis of all crystalline forms of compound 1 calcium salt that fall within the claimed scope.
Claims 26-29, 36-39, and 42-45 (which are dependent on claim 1) as well as claims 101-112 (which are dependent on claim 2) are also rejected for further requiring and/or reciting elements that are outside the scope of the enabling elements listed above.
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 36-39, 42-45, 105-112, 117-124, and 129-136 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 7, 11-17, and 23-27 of U.S. Patent No. 12,312,308 B2 (‘308B2)
Claims 7, 11-17, and 23-27 of ‘308B2 are directed towards a composition comprising a Compound 1 calcium salt and a pharmaceutically acceptable carrier or excipient. Although the Compound 1 calcium salt disclosed in ‘308B2 is in a crystalline form that differs from the crystalline form of Compound 1 calcium salt presently claimed, the claims of U.S. patent ‘308B2 also encompass compositions in which the Compound 1 calcium salt can be fully dissolved in an appropriate pharmaceutically acceptable carrier or excipient.
When a crystalline salt is fully dissolved in solution, the crystalline lattice is no longer present. Thus, the solution comprising a Compound 1 calcium salt as claimed in ‘308B2 would be indistinguishable from a solution comprising instant Compound 1 calcium salt.
Hence, even though the claims at issue are not identical, they are not patentably distinct from each other because there is overlap between the instant claims and the claim set from the granted patent.
Allowable Subject Matter
Claim 3 would be allowable upon correction of the above-noted objection.
Claims 113-116 are dependent on claim 3 and would be allowable upon correction of the above-noted objection for claim 3.
Claims 6 and 125-128 are allowed.
Conclusion
1, 2, 26-29, 36-39, 42-45, 101-112, 117-124, and 129-136 are rejected. Claims 3 and 113-116 are objected to. Claims 6 and 125-128 are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTEN ROMERO whose telephone number is (571)272-6478. The examiner can normally be reached M-F 9:30 AM - 6:00 PM ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JEFFREY H. MURRAY can be reached at (571) 272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624