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
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of PCT/EP2020/074241 filed August 31, 2020.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed on February 23, 2022. Foreign priority is claimed through European Patent Office 19306060.5 filed on September 2, 2019. All claims have been given an effective filing date of September 2, 2019.
Election/Restriction
Applicant’s election of Group II (Claims 11-16) and species election of A) a small molecule, particularly duloxetine, and B) aniridia in the reply filed on July 30, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Upon further consideration, Examiner withdraws the restriction requirement between Groups I and II and the species election requirements A and B as set forth in the Office action mailed on 03/06/2025. In view of the withdrawal of the restriction requirement, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Claim Status
Claim listing filed on February 23, 2022 is pending. Claims 1-7 and 10 are canceled. Claims 9 and 11 are amended. Claims 12-16 are new. Claims 8-9 and 11-16 are examined upon their merits.
Information Disclosure Statement
The information disclosure statement filed on February 23, 2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
Page 23, line 2: “eslsewhere” should recite “elsewhere.”
“Ritanserin” and “ritanserine” are alternative spellings and both are used throughout the specification. For consistency and clarity, Examiner recommends changing all instances of “ritanserine” to “ritanserin” because “ritanserin” is the accepted spelling in the art.
Pages 21-22, Figure Descriptions: Figures 1C and 4C are labeled in the drawings but are not described in the Figure Descriptions. MPEP § 608.01(f) states: “If the drawings show Figures 1A, 1B, and 1C and the brief description of the drawings refers only to Figure 1, the examiner should object to the brief description, and require applicant to provide a brief description of Figures 1A, 1B, and 1C.”
Appropriate correction is required.
Drawings
The drawings are objected to because Figures 3 and 5A-C are missing x-axis and/or y-axis labels which makes the plots unintelligible. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 11 is objected to because of the following informalities: “subject need thereof” should recite “subject in need thereof.” Appropriate correction is required.
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.
Claims 8-9 and 11-16 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.
Claims 8 and 11 recite “an agent which increases PAX6 gene and/or protein expression.” Claims 12 and 16 are dependent on Claim 11 and do not further define the claimed agent. This phrase is considered functional language because the feature (an agent) is defined by what it does (increases PAX6 gene and/or protein expression) rather than by what it is (MPEP § 7173.05(g)). To determine if functional language is ambiguous, the following factors are considered: (1) whether there is a clear-cut indication of the scope of the subject matter covered by the claim; (2) whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained; and (3) whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim. These factors are examples of points to be considered when determining whether language is ambiguous and are not intended to be all inclusive or limiting (MPEP § 7173.05(g)).
“Increases PAX6 gene and/or protein expression” only states a result obtained and is non-limiting in structure necessary to perform the stated function. Therefore, the metes about bounds of the agents cannot be readily determined, and Claims 8, 11-12, and 16 are rejected as being indefinite.
“An agent which increases PAX6 gene and/or protein expression” in Claims 8 and 11 is also considered relative terminology, specifically the term “increases” (MPEP § 2173.05(b)). Claims 9 and 12-16 are dependent on Claims 8 and 11 and do not further define the relative terminology. It is unclear what the threshold of “increase” is (2-fold increase? 4-fold increase?). It is also unclear what the “increase” is relative to (relative to a healthy control level? relative to a diseased state level?). The specification does not provide a definition of “increases PAX6 gene and/or protein expression” in such a way that one of ordinary skill in the art would understand what is claimed. Due to the relative terminology, Claims 8-9 and 11-16 are rejected as being indefinite.
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 8 and 11-16 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 claims contain 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.
The claims encompass both a genus of agents that increase PAX6 gene and/or protein expression and a genus of PAX6-related deficiency diseases. Specifically, claims 11, 13, and 16 are directed to a method for treating any type of PAX6-related deficiency disease by administering any agent which increases PAX6 gene and/or protein expression. Claim 8 is directed to a pharmaceutical composition comprising any agent which increases PAX6 gene and/or protein expression. Claim 12 is directed to treating aniridia and/or diabetes by administering any agent which increases PAX6 gene and/or protein expression. Claims 14-15 are directed to a method for treating any type of PAX6-related deficiency disease by administering duloxetine, ritanserin, topotecan, and/or a derivate thereof. The specification defines structural derivatives on pages 11-14. The specification defines “PAX6-related deficiency diseases” as any disease which has at least one deficiency in PAX6 gene and/or protein and can comprise autism, auditory defects, Turner syndrome, xeroderma pigmentosum, aniridia, diabetes, and other diseases (pages 4-5). The specification defines “treating” as “both prophylactic or preventive treatment as well as curative or disease modifying treatment” (page 3, first paragraph). “Therapeutically treating” will be used by Examiner in reference to treating that is distinct from preventing.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. In order to provide adequate written description and evidence of possession of this claimed method, the specification must provide sufficient distinguishing identifying characteristics of the method.
The specification teaches that ritanserin and duloxetine as single agents are able to rescue the production of endogenous PAX6 protein, PAX6-target gene expression, and cell migration of mutated limbal stem cells (page 24; Figures 4-5). Topotecan was able to rescue PAX6 gene expression at the RNA level (page 24; Figures 1-3). Overall, duloxetine and ritanserin as single agent stabilize PAX6 protein while topotecan enhances PAX6 transcription (page 24).
However, none of these working examples characterize agents that directly or indirectly increase PAX6 gene and/or protein expression other than duloxetine, ritanserin, and topotecan. While increasing PAX6 expression by administering RNA therapy is a known approach to therapeutically treat aniridia and diabetes (as evidenced by Yongblah et al. Mol Ther Nucleic Acids. Sept. 1 2018), the specification does not teach the treatment of any other PAX6-related deficiency diseases nor the prevention of any PAX6-related deficiency diseases.
Therefore, claims 8 and 11-16 are rejected for insufficient written description, because the claims contain subject matter which was not described in the specification in such a way as to reasonably convey that the inventor had possession of the claimed invention at the time of filing.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claims 8 and 11-16 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 therapeutically treating aniridia and/or diabetes by administering duloxetine, ritanserin, and/or topotecan, does not reasonably provide enablement for treating and/or preventing any type of PAX6-related deficiency disease by administering any agent that increases PAX6 gene and/or protein expression. 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.
MPEP § 2164.01(a) states that 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, but are not limited to:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims and nature of the invention:
The nature of the invention is complex, encompassing the treatment and/or prevention of any type of PAX6-related deficiency disease by administering any agent which increases PAX6 gene and/or protein expression (Claims 11, 13, and 16). Claim 8 is directed to a pharmaceutical composition comprising any agent which increases PAX6 gene and/or protein expression. Claim 12 is directed to treating aniridia and/or diabetes by administering any agent which increases PAX6 gene and/or protein expression. Claims 14-15 are directed to a method for treating any type of PAX6-related deficiency disease by administering duloxetine, ritanserin, topotecan, and/or a derivate thereof. The claims encompass both a genus of agents that increase PAX6 gene and/or protein expression and a genus of PAX6-related deficiency diseases.
When analyzing the scope of enablement, the claims are analyzed with respect to the teachings of the specification and are to be "given their broadest reasonable interpretation consistent with the specification." See MPEP 2111 [R-5]; Phillips v. AWH Corp., 415 F.3d 1303, 75 USPQ2d 1321 (Fed. Cir. 2005); and In re Hyatt, 211 F.3d 1367, 1372, 54 USPQ2d 1664, 1667 (Fed. Cir. 2000). Applicant always has the opportunity to amend the claims during prosecution, and broad interpretation by the examiner reduces the possibility that the claim, once issued, will be interpreted more broadly than is justified. In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550- 51 (CCPA 1969).
The state of the prior art and level of predictability in the art:
The level of predictability in the art depends, most importantly, on whether the claimed invention can be practiced by one of ordinary skill in the art. Yongblah et al. Mol Ther Nucleic Acids. Sept. 1 2018 teaches that an RNA-based therapy (miR-7 and miR-375) that increases the expression of PAX6 protein levels can be used to therapeutically treat aniridia (abstract). Yongblah further teaches that mutations in PAX6 are known to cause diabetes, and increasing the expression of PAX6 in pancreatic cells by administering miR-7 and miR-375 has therapeutic implications in treating diabetes (page 148, paragraph 2).
While the state of the art prior to filing provides enablement for therapeutically treating aniridia and diabetes by administering miR-7 and miR-375 RNA-therapy that increases PAX6 expression, no enabling guidance is provided for (1) the treatment of PAX6-related deficiency diseases other than aniridia and diabetes; (2) agents that increase PAX6 gene and/or protein expression other than miR-7 and miR-375; nor (3) the prevention of any type of PAX6-related deficiency disease. Even after the effective filing date, the state of the art teaches the inability to prevent aniridia and diabetes. Specifically, Maguire 2023 teaches that aniridia cannot be prevented because it is a hereditary and congenital eye disorder (under ‘Can it be prevented?’). The US Center for Disease Control 2024 teaches that type 1 diabetes can be effectively treated, but it cannot be prevented (Key Points). There is no support in the Applicant’s disclosure leading one of ordinary skill to overcome these deficiencies.
Level of skill in the art:
The level of skill would be high encompassing gene therapy, functional protein assays, long-term in vivo prevention experiments, etc.
Amount of direction provided by inventor and the existence of working examples:
The specification teaches that ritanserin and duloxetine as single agents are able to rescue the production of endogenous PAX6 protein, PAX6-target gene expression, and cell migration of mutated limbal stem cells (page 24; Figures 4-5). Topotecan was able to rescue PAX6 gene expression at the RNA level (page 24; Figures 1-3). Overall, duloxetine and ritanserin as single agents stabilize PAX6 protein while topotecan enhances PAX6 transcription (page 24).
The specification offers no examples of treating or preventing any disease. Because Yongblah 2018 establishes a nexus between increasing PAX6 expression and the treatment of the aniridia and diabetes, and the specification teaches that ritanserin, duloxetine, and topotecan increase PAX6 expression, the specification in light of the state of the art prior to filing is enabled for therapeutically treating aniridia and/or diabetes by administering duloxetine, ritanserin, and/or topotecan. However, treating and/or preventing any type of PAX6-related deficiency disease by administering any agent that increases PAX6 gene and/or protein expression is not enabled by the specification nor the state of the art prior to filing. A person having ordinary skill in the art would have to make a substantial inventive contribution in order practice the claims as there is no guidance within the disclosure as filed pertaining to this embodiment.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
Given that the nature of the claims is in vivo treatment and prevention, a person having ordinary skill in the art would have to perform multiple further experiments, in human clinical trials or in animal models, that are predictive of treatment and prevention in a representative number of PAX6-related deficiency diseases by administering a representative number of agents that increase PAX6 gene and/or protein expression in order to demonstrate the invention could be used with a reasonable expectation of success. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of success. Therefore, Claims 8 and 11-16 are rejected for lack of enablement.
Claim Rejections - 35 USC § 102
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 8-9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Christensen WO 1999/06031 (of record in the restriction requirement filed 03/06/2025).
The instant claims recite a pharmaceutical composition comprising an agent which increases PAX6 gene and/or protein expression (Claim 8) wherein the agent is topotecan (Claim 9).
Christensen teaches a pharmaceutical composition comprising topotecan (abstract).
Therefore, Claims 8-9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Christensen.
Allowable Subject Matter
No claim is allowed. However, a method of therapeutically treating (distinct from preventing) diabetes and/or aniridia by administering duloxetine, ritanserin, topotecan, and/or a derivate thereof is both enabled and free of the prior art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH COOPER PATTERSON whose telephone number is (703)756-1991. The examiner can normally be reached Monday - Friday 8:00am - 5:00pm EST.
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 Stucker can be reached at (571) 272-0911. 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.
/SARAH COOPER PATTERSON/ Examiner, Art Unit 1675
/STACEY N MACFARLANE/ Examiner, Art Unit 1675
Prosecution Insights