EXAMINER'S AMENDMENT
The application has been amended as follows:
The status identifier for claim 44 has been changed to currently amended.
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 .
The examiner of your application in the PTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Brian Whiteman, Art Unit 1636.
The status identifier for claim 44 was incorrect because the claim was amended. The identifier was corrected by instructions in an examiner’s amendment. See MPEP 714(I)E.
Election/Restrictions
Applicant’s election without traverse of group IX (claims 11, 12, 44 and 45) and species diabetic retinopathy in claim 11 and SEQ ID NO: 104 in claim 44 in the reply filed on 11/5/25 is acknowledged. Upon further consideration, the species requirement is withdrawn and all of the non-elected species in claims 11 and 44 are rejoined with the elected species and examined.
No claims are currently withdrawn because the claims directed to non-elected inventions were cancelled in the amendment filed on 11/5/25.
Information Disclosure Statement
The report on patentability of the IPEA and/or ISA has been considered by the examiner.
The references cited in the PCT international search report by the United States have been considered, but will not be listed on any patent resulting from this application because they were not provided on a separate list in compliance with 37 CFR 1.98(a)(1). In order to have the references printed on such resulting patent, a separate listing, preferably on a PTO/SB/08 form, must be filed within the set period for reply to this Office action.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
In view of the description for figures disclosing red or blue, did they applicant intend to file color drawings? See description for Figure 1A-1C. If applicant intended to file color drawings, see the following paragraphs.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See pages 73 and 103-108.
On pages 6 and 58, the specification discloses that the siRNA can be N-187951-01, 18795-02, 18795-03, 187951-04. The claims were amended to indicate that these siRNA are SEQ ID NOs: 95-98, but the specification still recites these designations. Suggest adding these SEQ ID NOs: to these designations to help clarify the sequences.
The disclosure is objected to because of the following informalities: The description of Figure 1 and 16 indicate that there are colors in the drawings. Did the applicant intend to file color drawings? Clarification is requested.
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.
Claims 11, 12, 14, and 44-45 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.
The claimed invention embraces a genus of agents that inhibitors one biological activity of the long non-coding RNA HOTAIR, wherein a therapeutically effective amount of the at least one agent inhibits at least one biological activity of the long non-coding HOTAIR to treat a condition, wherein the condition is one or more of: diabetic retinopathy (DR), diabetic macular edema, diabetic nephropathy, diabetic cardiomyopathy, diabetic neuropathy, proliferative vitreoretinopathies, neovascular glaucoma, ischemic retinopathy, retinopathy secondary to retinal vein occlusion, age-related macular degeneration, and intraocular tumors.
HOTAIR is a long non-coding RNA transcript found in humans. Page 21 discloses three known human HOTAIR transcripts.
Pages 6-7 and 55-58 disclose potential agent that could be embraced by the genus of agents, including HOTAIR inhibitors, e.g., antibodies, siRNA (SEQ ID NOs: 95-98 and 104, 106, 108, 110), piRNA, snRNA, a miRNA, a ribozyme, an antisense oligonucleotide, and small molecules (DZNep and 5-aza-dC). Page 55 cites prior art to indicate that various types of inhibitors are known in the prior art for inhibiting nucleic acid function. NOTE: a search of the publications, indicates that there appears to be directions to making various types of nucleic acid inhibitors, but none of the publications appear to disclose that HOTAIR nucleic acid inhibitors were well known in the prior art. Pages 98-99 provide a prophetic example for identifying compounds with an inhibitory effect on HOTAIR expression.
Page 58 also provides a definition for the “effective amount”.
With respect to the agent set forth in claim 45, the skilled artisan would possess the knowledge that agents were readily available for use in treating conditions associated with diabetes-induced neovascularization, including anti-inflammatory agents, anti-VEGF therapy, MMP inhibitors, steroids and NSAIDs.
With respect to the claimed method, the specification of the instant disclosure only has written support for treating diabetic retinopathy (DR) in a subject in need thereof comprising administering a HOTAIR inhibitor selected from antisense oligonucleotides, siRNA, and shRNA that comprise a sequence that is complementary to a HOTAIR RNA transcript, but does not have written support for treating all the claimed conditions. The diseases set forth in instant claim 11 require a different subject and the role of lncRNA HOTAIR in each disease could be different. Qi et al. (Experimental and Therapeutic medicine 16: 4817-4823, 2018) teach that LncRNA HOTAIR improves diabetic cardiomyopathy. Each condition set forth in the claimed invention appears to be associated with angiogenesis. However, the expression and role of lncRNA HOTAIR in different tissues or diseases might be different. US 20250041444 discloses, “Overexpression of lncRNA HOTAIR improves a cardiac function in diabetic cardiomyopathy, reduces oxidative stress and inflammation, and alleviates cardiomyocyte death (paragraph 5).” Also, as disclosed in the prior art (Qi et al., supra) and currently, overexpression of lncRNA HOTAIR can treat diabetic cardiomyopathy in a subject in need thereof. The prior art indicates that the role on HOTAIR and angiogenesis is limited, mostly directed to cancer. In view of the lack of teaching in the specification for what claimed conditions are/are not associated expression of lncRNA HOTAIR, a skilled artisan would have to further experiment with each condition and determine if the agent can treat the condition.
Pages 6-7 and 55-58 contemplate nucleic acid inhibitors, including antisense oligonucleotides, miRNA, ribozymes, siRNA. The genus of nucleic acid inhibitors embrace antisense oligonucleotides, aptamers, ribozymes, microRNAs, anti-microRNA molecules. Neither specification nor the prior art describe any HOTAIR inhibitors that are aptamers, ribozymes, microRNAs, anti-microRNA (antagomirs) molecules. Page 6 provides SEQ ID NOs: 61-71 that are sequences for HOTAIR siRNAs. While the specification provides written support for HOTAIR inhibitors selected from antisense oligonucleotides, siRNA, and shRNA that comprise a sequence that is complementary to a HOTAIR RNA transcript and methods for identifying potential HOTAIR that inhibit at least one biological activity of the long non-coding HOTAIR, the specification does not provide written support for a genus of HOTAIR compounds that can treat a condition embraced by the claimed method.
The specification does not provide a description of species of agents, including small molecules, antibodies or aptamers, ribozymes, miRNAs that are considered an inhibitor that inhibits at least one biological activity of lncRNA HOTAIR. Even though the specification of the instant application provides a HOTAIR sequence and there are methods known in the art to make compounds (antibodies, aptamer, ribozyme), there is no written description for the genus of HOTAIR compounds that can treat the instant conditions in a patient. See Amgen Inc. V. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give]the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. V. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011) (patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties). See MPEP 2163(B)(II)(3).
The written description requirement for the claimed genus of agents and methods is not satisfied because the specification does not provide sufficient description of a representative number of species. The species of lncRNA HOTAIR inhibitors and methods set fort in claim 11 are not adequately described and the description of siRNA is not representative of the entire genus of inhibitors. There is a substantial variation within the genus of methods and inhibitors and the specification does not describe a sufficient variety of species to reflect the variation within the genus. See Enzo Biochem., 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)(“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). See also MPEP §2163.
In view of the foregoing, it is clear that the specification of the instant disclosure fails to convey to the skilled artisan that the applicant had possession of the claimed genus of method and/or agents in the instant claims as of the effective filing date.
Claims 11, 14, and 44-45 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 treating diabetic retinopathy (DR) in a subject in need thereof comprising directly administering to an eye of the subject at least one agent that inhibits at least one biological activity of the long non-coding RNA HOTAIR to treat DR, does not reasonably provide enablement for treating using diabetic macular edema, diabetic nephropathy, diabetic cardiomyopathy, diabetic neuropathy, proliferative vitreotinopathies, neovascular glaucoma, ischemic retinopathy, retinopathy secondary to retinal vein occlusion, age-related macular degeneration and intraocular tumour using the at least one agent. NOTE: the scope of enablement does indicate that there is written support for this scope. 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.
The claimed broadly reads on using a genus of agents to treat DR, diabetic macular edema, diabetic nephropathy, diabetic cardiomyopathy, diabetic neuropathy, proliferative vitreotinopathies, neovascular glaucoma, ischemic retinopathy, retinopathy secondary to retinal vein occlusion, age-related macular degeneration and intraocular tumour, wherein the agent inhibits at least one biological activity of the long non-coding RNA HOTAIR.
State of the Art:
Zhao et al. (Clinical Science 134, 2419-2434, published September 8, 2020) disclose studies that indicate that HOTAIR is a potential therapeutic target of DR.
Qi et al. (Experimental and Therapeutic medicine 16: 4817-4823, 2018) teach that LncRNA HOTAIR improves diabetic cardiomyopathy.
Niknam et al. (Reports of Biochemistry & Molecular Biology 12, 448-457, 2023) reports that circulating levels of HOTAIR-lncRNA are associated with disease progression and clinical parameters in type 2 diabetes patients. The lncRNA can be a potential marker for early diagnosis and prognosis of type 2 diabetes (T2D). Niknam does not teach that the HOTAIR-lncRNA is considered a therapeutic target for treating T2D.
Wu et al. (Reproduction, Fertility, and Development, 2019, 31, 377-385) teach that lncRNA HOTAIR suppresses the angiogenesis of human placentation by inhibiting VEGF A expression. HOTAIR may represent a potential therapeutic target for patients with human placental vascularization abnormalities. Wu et al. also discuss that little is known about the regulatory role of long non-coding RNAs and their relevance to human diseases (page 377).
Overexpression of lncRNA HOTAIR improves a cardiac function in diabetic cardiomyopathy, reduces oxidative stress and inflammation, and alleviates cardiomyocyte death (US 20250041444, paragraph 5).
In view of the prior art, there appears to be unpredictability with HOTAIR lncRNA and its role in human diseases, including the disease embraced by the claimed invention.
With respect to the agent set forth in claim 45, the skilled artisan was aware of agents that could be used for treating conditions associated with diabetes-induced neovascularization.
The prior art does not appear to teach using an inhibitor of HOTAIR lncRNA to treat any of the conditions set forth in the claimed method.
Working examples:
An in vitro working example shows that HOTAIR siRNA reduced branching and total number of tubules in normoglycemia (NG) and hyperglycemia (HG) conditions (FIG 4B and 4C). “Even more intriguing at the 6-hour mark, when HRECs were pre-treated with siHOTAIR, the presence of both exogenous VEGF proteins and HG were not able to completely recover the degree of branching and number of tubules compared to HG controls, which implies that the knockdown of HOTAIR may be further desensitizing ECs to other external angiogenesis-causing factors in HG.” The specification provides working examples showing that siRNA HOTAIR can be used to treat DR in a murine model of DR using directly administration of the siRNA to the mice.
Breadth of the claims:
The diseases set forth in instant claim 11 require a different subject and the role of lncRNA HOTAIR in each disease could be different. Each condition set forth in the claimed invention appears to be associated with angiogenesis. However, the expression and role of lncRNA HOTAIR in different tissues might be different. The prior art indicates that the role on HOTAIR and angiogenesis is limited. For example, as disclosed in the prior art (Qi et al., supra) and currently, overexpression of lncRNA HOTAIR can treat diabetic cardiomyopathy in a subject in need thereof. In view of the lack of teaching in the specification for what claimed conditions are/are not associated expression of lncRNA HOTAIR, a skilled artisan would have to experiment with each condition and determine if the agent can treat the condition. It appears that the specification was not fully enabled for using the methods steps in the claimed. See MPEP 2164.05(a)-(b).
With respect to genus of administration routes, several of the conditions embraced by the claimed invention involve an eye, heart, kidney, nerves of the subject. For the reasons set forth above, it appears that the specification is only enabled for treating DR in a subject in need thereof. The specification provides a working example of intravitreal injection of a HOTAIR siRNA in a murine model of DR. This is not considered to enable other routes to treat DR in a subject in need thereof because there are issues with other routes for delivering an oligonucleotide to the eye of a subject in need thereof. Zhang et al. teaches that direct administration to the eye is only successful route for delivering an oligonucleotide therapeutically to a subject (Trends in Biotechnology 2024, Vol. 42, 1439-1452). One of skill in the art could not reasonably extrapolate from the working example to the treating the claimed conditions using any route of administration without an undue amount of experimentation.
While the claims do not have written description for a genus of agents that inhibit at least one biological activity of the lncRNA HOTAIR, it would not take an undue amount of experimentation to make and use a sufficient number of agents to inhibit at least one biological activity of the lncRNA HOTAIR. One of skill in the art could use screening methods to arrive at these agents or order a biotechnology company to make the agent.
Even though claim 11 is not considered fully enabled, the combination method dependent in claim 45 is considered enabled because there are therapeutic agents that can treat diabetes-induced neovascularization in the subject well known in the prior art. The prior art does not disclose that administering an agent that inhibits at least biological activity of lncRNA HOTAIR would interfere with a known therapeutic agent for treating these conditions.
Thus, the claimed method is not fully enabled.
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.
Claim 45 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.
Claim 45 recites the limitation "the condition associated with diabetes-induced neovascularization" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim.
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 11, 12, 44, and 45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 85-104 of copending Application No. 19454863(reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both set of claims embrace using HOTAIR siRNA to treat diabetic retinopathy in a subject. Several siRNA reads on the siRNA set forth in instant claim 44. See claims 88 and 101 of ‘863. SEQ ID NOs: 28, 32, and 27 read on instant SEQ ID NO: 110. SEQ ID NOs: 26 and 31 read on instant SEQ ID NO: 108. SEQ ID NOs: 24 and 30 read on instant SEQ ID NO: 106. SEQ ID NOs: 22 and 29 read on SEQ ID NO: 104.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
See attached PTO-326 for disposition of claims.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. US 20180148720 discloses a dsRNA comprising SEQ ID NO: 23 that comprises instant SEQ ID NO: 98, but ‘720 does not teach or suggest using the dsRNA to treat any condition set forth in the instant claims. At the time of filing, the prior art did not appear to teach or suggest using lncRNA HOTAIR inhibitors to treat the conditions set forth in the instant claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brian Whiteman whose telephone number is (571)272-0764. The examiner can normally be reached on Monday thru Friday; 6:00 AM to 3:00PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at (571)-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636
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