0DETAILED 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 no., under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Status of Application/Amendment/Claims
This Office action is in response to the communications filed on July 01, 2026.
Currently, claims 1-11 are pending in the instant application. Claim 1 has been amended to include additional limitations in response to the non-final Office Action mailed, 03/03/2026. Specifically, claim 1 is amended to clarify the subject being treated is a human subject, and that the human MCT8 being introduced to the subject is a functional human MCT8 polypeptide encoded by the SLC 16A2 gene and that is capable of transporting thyroid hormone across a cell membrane. Applicant’s statement that “support for these amendments is found throughout the application as filed, including without limitation at page 1, lines 23-32; page 2, lines 1-18; page 2, line 30 to page 3, line 8; page 3, lines 18-23; page 7, line 27 to page 8, line 7; page 10, lines 15-28; page 11, line 18 to page 14, line 14; and page 15, lines 8-12,” and that “no new matter is introduced in these amendments,” is acknowledged.
Response to Arguments and Amendments
Withdrawn Objections and Rejections
Any objections or rejections not repeated in this Office action are hereby withdrawn.
New Grounds of Rejection Necessitated by Amendment
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 1, 3, 5, 7-8, and 10 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 method of treating Allan-Herndon-Dudley syndrome, the method comprising determining that a human subject is in need of treatment of Allan-Herndon-Dudley syndrome; and administering by intravenous injection a gene therapy to introduce a normal human MCT8 into the human subject’s cells to increase T3 in the subject's brain and induce a T3-mediated response, wherein the normal human MCT8 is introduced using a viral vector AAV9, and wherein the normal human MCT8 is a functional human MCT8 polypeptide encoded by the SLC16A2 gene and that is capable of transporting thyroid hormone across a cell membrane, does not reasonably provide enablement for treating a human subject with Allan-Herndon-Dudley syndrome using any vector encoding a normal human MCT8 administered by any route. 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.
The breadth of claims: the claims allow the use of any vector and any route of administration to deliver a normal human MCT8 to a human subject afflicted with Allan-Herndon-Dudley syndrome.
The nature of the invention: The invention restores functional MCT8 by gene therapy so thyroid hormone transport improves in the brain, and it pairs that approach with DITPA and/or TRIAC to reduce peripheral thyroid-hormone excess. In the animal studies, IV AAV9-MCT8 increased brain T3 content and improved motor/cognitive outcomes, supporting the gene-therapy arm. DITPA is used separately or in combination to normalize serum T3 and address metabolic abnormalities. Together, the two therapies are presented as complementary: one improves CNS thyroid delivery, the other helps control systemic thyrotoxicosis.
State of the prior art: AAV9 is a well-characterized, FDA-approved, human BBB-crossing platform when administered by IV. The prior art further establishes that when the AAV9-MCT8 construct is delivered by ICV or IV injections into neonatal Mct8-KO (MCT8−/y) mice, an increase occurs in brain TH signaling upon IV, but not ICV, delivery, see Iwayama (THYROID 26(9) pp 1311-1319, provided in IDS, published 23 Aug., 2016). Furthermore, the art establishes the human blood brain barrier is unique and that model organisms and human in vitro systems cannot directly predict specific functional performance in human blood-brain barrier crossing due to species differences and functional unknowns, but they help guide therapeutic avenues, see O'Brown NM, et al,(Genes Dev. 2018 Apr 1;32(7-8):466-478).
The level of one of ordinary skill: A highly trained MD or PhD level research scientist with significant postdoctoral experience specialized in viral vector technology and complex human anatomy and systems.
The level of predictability in the art: the art has established that aside from IV delivery of the claimed functional human MCT8 polypeptide encoded by SCL16A2 gene using the claimed AAV9 viral vector, other methodologies such as alternative administration routes, alternative isoforms, and alternative vectors are unpredictable in the ability to achieve the claimed functional limitations, see Iwayama.
The amount of direction provided by the inventor: the inventors provide adequate direction in achieving the claimed functional limitations when intravenously administering AAV9-hMCT8, but do not provide direction for other routes of administration or other vectors systems.
Working examples: The specification provides working examples only for IV delivery of AAV9-hMCT8 to treat a mouse model that recapitulates human Allan-Herndon-Dudley syndrome (specification pg. 10 lines 19-24: “Previous experience indicated that IV delivery is more feasible compared to ICV delivery, as IV is a simpler route and would target not only the brain but other body regions that express MCT8 such as the liver. Therefore, we tested IV delivery…,” and specification pg. 33 lines 12-13: “we resorted to gene therapy using an adeno-associated virus serotype 9 (AAV9) vector … that is FDA approved.”).
The quantity of experimentation needed to make or use the invention based on the content of the disclosure: to practice the invention as claimed in a Human subject, there would be undue experimentation. The claims allow for any route of administration and any vector delivery platform. Thus, an artisan would have to engage in open-ended experimentation to determine which combination of administration route and vector technology would effectively cross the human blood brain barrier to enable the claimed functional limitations of the invention.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-11 are rejected under 35 U.S.C. 103 as being unpatentable over Iwayama H, et. al., (THYROID 26(9) pp 1311-1319, provided in IDS, published 23 Aug., 2016) in view of Verge CF, et. al., (J Clin Endrocinol Metab, 97(12):4515-4523, published 19 Sept, 2012), and Groeneweg S et al. (Lancet Diabetes Endocrinology, 7:695-706, provided in IDS, published 31 July, 2019).
Regarding claim 1, Iwayama teaches a method of treating Allan-Herndon-Dudley syndrome the method comprising determining that a subject is in need of treatment for Allan-Herndon-Dudley syndrome (abstract: “This proof-of-concept study examined whether transfer of human MCT8 (hMCT8) cDNA …could correct the brain defects of Mct8 knockout mice (Mct8KO).” Introduction: “Defective MCT8 proteins reduce TH transport into the brain, producing tissue TH deprivation and delayed myelination. This form of sex-linked mental retardation has been named the Allan–Herndon–Dudley syndrome”); and administering gene therapy to introduce normal human MCT8 into the subject's cells to increase T3 in the subject's brain and induce a T3-mediated response (discussion: “IV-delivered AAV9-ShMCT8 increased brain T3 content and produced concomitant changes in the TH controlled gene, Hr, within Mct8KO mice”), wherein the normal human MCT8 is a functional human MCT8 polypeptide encoded by the SCL16A2 gene (Introduction: “MCT8 (SLC16A2) gene,… human MCT8 (hMCT8)” results: “as AAV9 clearly delivered hMCT8 protein to the mouse brain, next the functionality of this protein was verified.”) and that is capable of transporting thyroid hormone across a cell membrane (introduction: MCT8… which encodes a cell membrane protein that serves as a specific transporter of thyroid hormone (TH);” discussion reporting that IV-delivered AAV9-ShMCT8 increased brain T3 content and induced expression of the TH-responsive gene Hr, evidencing that the delivered hMCT8 protein was functional and capable of transporting thyroid hormone across the cell membrane, as an increase in intracellular T3-driven transcriptional activity necessarily follows from TH crossing the plasma membrane). Regarding “human subject”: Iwayama does not expressly perform its gene therapy method on a human subject, as its experiments are conducted in MCT8 KO mice. However, Iwayama expressly contemplates and states the work is directed toward development of “a successful gene therapy for patients with MCT8 deficiency” (page 1318, second column, second full paragraph), and further states the results demonstrate “the first report of successful delivery of MCT8 in vivo through a viral vector” that “could potentially induce MCT8 transcription and translation into a functional protein that could transport TH in vivo (page 1317, first column, last paragraph and page 1317, second column, last paragraph).
Regarding claim 2, Iwayama teaches the normal human MCT8 is introduced using a viral vector AAV9 (abstract: “The current study examined the efficacy of an AAV9 vector to transfer the short (S) and the long (L) hMCT8 cDNA (AAV9-ShMCT8 and AAV9-LhMCT8, respectively) to the Mct8KO mouse at postnatal day 1 (P1) using either intravenous (IV) or intracerebroventricular (ICV) delivery”).
Further regarding claims 1 and 2, while Iwayama doesn’t expressly recite a step of determining that a human subject is in need of treatment for Allan-Herndon-Dudley syndrome, the Mct8 knockout mouse model described by Iwayama are well-established animal models of Allan-Herndon-Dudley syndrome and exhibit the neurological and thyroid hormone abnormalities characteristic of the disorder; thus, the mouse model subjects are determined to be in need of treatment for AHDS prior to administering the disclosed MCT8 gene therapy. Furthermore, the mouse model is recognized in the art including by Iwayama itself, as predictive models for development of gene therapy intended for human patients with the disease.
Regarding claims 3-11, Iwayama teaches “treatment of affected children with a combination of levothyroxine (LT4), propylthiouracil (PTU), or the thyromimetic compound diiodothyropropionic acid (DITPA) reduces the hypermetabolism and ameliorates nutrition, but does not produce significant neurodevelopmental improvements”; however, AAV9 is “a good candidate for viral transfer of MCT8 into the MCT8-deficient brain.”
Iwayama does not teach use of DITPA +/- TRIAC in combination with MCT8 gene therapy, administration of DITPA to the subject begins at one dose for two weeks and continues for at least two weeks at a higher dose, or each of the one dose and the higher dose administered to the subject is determined based on T3 serum levels of the subject.
Verge teaches the use of DITPA in the treatment of MCT8 deficiency and that DITPA normalizes the elevated serum T3. Verge further teaches administration of DITPA to the subject begins at one dose for two weeks and continues for at least two weeks at a higher dose (discussion: “a 24-wk course of DITPA, given in incremental doses of 90 mg/d (45 mg twice daily) each for 2wk, reaching a maximal dose of 360 mg (on the average 3.75 mg/kg - d) on the eighth week.”). Verge further teaches that serum T3 levels are monitored after DITPA administration, which correlates with “the decline in serum T3” (See FIG.3).
Groeneweg teaches “in the 45 patients [with MCT8 deficiency] assessed for the primary endpoint, serum T3 concentrations had significantly decreased by month 12” following TRIAC treatment (See page 699). Groeneweg further teaches that TRIAC therapy may be administered by “individualized dose-escalation… with a goal of attaining serum total T3 concentrations within the target range” (See page 697).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to first determine that a human subject is in need of treatment for Allan-Herndon-Dudley syndrome and then administer the MCT8 gene therapy of Iwayama to a human subject alone or in combination with DITPA in the escalading dosing regimen beginning at a first dose for two weeks and continuing for at least two weeks at a higher dose..
Iwayama teaches that AAV9-mediated MCT8 gene therapy increases T3 content in the brain and induces T3-responsive gene expression in Mct8KO mice, thereby addressing the central thyroid hormone deficiency characteristic of AHDS. It was well established in the art prior to the effective filing date that MCT8 deficiency is characterized not only by cerebral hypothyroidism but also by peripheral thyrotoxicosis, including elevated serum T3 levels. Verge teaches that administration of DITPA to subjects with MCT8 deficiency lowers elevated serum T3 levels and ameliorates peripheral hyperthyroid manifestations. Verge further teaches a specific incremental dosing regimen of DITPA administered in two-week intervals at increasing dose levels in subjects with MTC8 deficiency, demonstrating that such escalation protocols were known and clinically implemented in this disease context. Accordingly, a person of ordinary skill in the art would have been motivated to combine the brain-directed gene therapy of Iwayama with the serum T3-lowering therapy of Verge in order to address both the central and peripheral components of MCT8 deficiency, with a reasonable expectation of success. Furthermore, since the serum T3 levels are indicative of DITPA efficacy, one of ordinary skill (e.g., medical doctor) in the relevant art (i.e., medical field) to the claimed therapeutic method would readily and reasonably understand that the dose optimization of DITPA should correlate with serum T3 levels, which were known to be continuously monitored as disclosed in Verge, in order to limit known adverse effects of DITPA treatment. This represents the combination of a known techniques (DITPA dose escalation to normalize serum T3 and MCT8 gene therapy to normalize brain T3 content) and dosing regimen to a known disease state in which both central and peripheral thyroid hormone abnormalities were recognized.
Given Iwayama’s express statement that the AAV9-ShMCT8/IV delivery approach is directed at eventual treatment of human MCT8-deficient patients, and given that MCT8 KO mouse models are well-established, art-recognized surrogate models for human Allan-Herndon-Dudley syndrome, a PHOSITA would have been motivated with a reasonable expectation of success, to extend Iwayama’s successful murine embodiment (AAV9-ShMCT8, IV delivery) to a human subject presenting with AHDS. This represents the application of a known technique (AAV9-mediated gene therapy, already shown by Iwayama to produce a functional, membrane transporting MCT8 protein and a corresponding T30mediated response in an art-accepted animal model of the human disease) to treat the analogous human disease that the animal model was developed to represent, with a reasonable expectation of success.
It would have been obvious to further administer TRIAC in addition to the MCT8 gene therapy and DITPA. Groenewegen teaches the use of TRIAC as an additional thyroid hormone analog capable of modulating thyroid hormone signaling in MCT8 deficiency. Given that both DIPA and TRIAC were well recognized as small molecule agents that lower serum T3 in MCT8 deficiency a person of ordinary skill in the art would have been motivated with a reasonable expectation of success to further include TRIAC in addition to DITPA as small molecule agents in combination with AAV9-MCT8 gene therapy in order to provide an additive or greater reduction in serum T3, which is one of the hallmarks of MCT8 deficiency so as to improve or enhance the therapeutic outcome in the subject in need of treatment for AHDS. That is, one skilled in the art would have reasonably deemed that two agents that reduce serum T3 levels/concentrations would provide a greater level of reduction in serum T3 when compared to just one agent, DIPTA.
Applicant Arguments Regarding Rejections under 35 U.S.C. § 103
Applicant's arguments filed 07/01/2026 have been fully considered but they are not persuasive.
Applicant argues that “Iwayama's indefinite and expressly inconsistent and indefinite results with mice does not genuinely render obvious the claimed treatment of human subjects,” characterizing the reference as too unpredictable to support a reasonable expectation of success in human subjects. This argument is not persuasive because obviousness does not require that every embodiment disclosed in a reference succeed, only that the reference render obvious the claimed embodiment. Iwayama’s IV-delivered AAV9-ScMCT8 embodiments succeeded, increasing brain T3 content and inducing expression of the TH-responsive gene Hr, and Iwayama expressly identifies this as evidence of a functional, membrane-transporting MCT8 protein. The failure of other embodiments (AAV9-LhMCT8, ICV delivery) does not undermine the motivation to extend the successful embodiment; if anything, it teaches a skilled artisan toward the specific combination of isoform and delivery route that worked and away from those that did not. Moreover, Iwayama expressly states that the findings are directed toward development of “a successful gene therapy for patients with MCT8-deficiency” (page 1318), which is an explicit motivation to extend the Iwayama’s murine “proof-of-concept” to human patients, and supports a reasonable expectation of success in applying the successful embodiment to a human subject, particularly given that MCT8KO mice are an art-recognized model for the human disease.
Applicant further argues that Verge and Groeneweg “were not cited to fill any of the gaps in Iwayama’s disclosure” and that no motivation exists to combine the references. This argument is not persuasive because Verge and Groeneweg were not cited to cure any deficiency regarding the “human subject” or “capable of transporting thyroid hormone” limitations of claim 1, rather these limitations are already addressed by Iwayama’s disclosure as set forth above. Verge and Groeneweg were properly cited, as in the prior Office Action, to supply the DIPTA/TRIAC dosing and combination limitations of claims 3-11, and the stated rationale for combining these references with Iwayama, namely, addressing the peripheral (i.e., serum T3) component of MCT8 deficiency in combination with Iwayama’s brain-directed gene therapy, remains unrebutted. Applicant’s response does not address this specific rational, but merely asserts in conclusory fashion that no motivation exists. A general allegation that references fail to disclose or suggest the claimed subject matter, without addressing the specific reasoning of record, does not constitute a substantive rebuttal.
Maintained Rejections
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 1-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-8, and 16 of copending Application No. 19299711 in view of Iwayama H, et. al., (THYROID 26(9) pp 1311-1319, provided in IDS, published 23 Aug., 2016), Verge CF, et. al., (J Clin Endrocinol Metab, 97(12):4515-4523, published 19 Sept, 2012), and Groeneweg S et al. (Lancet Diabetes Endocrinology, 7:695-706, provided in IDS, published 31 July, 2019).
The copending claims are drawn to a method of treating Allan-Herndon-Dudley syndrome, the method comprising administration of 3,5-diiodothyropropionic acid (DITPA) to a subject in need thereof, wherein administration is in a total daily dosage of about 2.5 milligrams per kilogram of body weight of the subject, and wherein the administration reduces triiodothyronine (T3) serum levels to normal, increases T3 brain levels to normal, increases or maintains normal serum levels of thyroxine (T4) and decreases or maintains normal thyroid stimulating hormone (TSH) serum levels. See the additional copending claims for additional limitations of the instant dependent claims.
To the extent that there are limitations of the instant claims that are not taught by the copending claims, the teachings of Iwayama, Verge, and Groeneweg are discussed above. Given the substantially similar subject matter between the copending claims and the teachings of Iwayama, Verge, and Groeneweg, it would have been obvious to have modified the subject matter of the copending claims in the manner discussed above to arrive at the instant claims for substantially the same reasons as discussed above. It was well-established in the art at the time of filing that AHDS driven by MCT8 deficiency is characterized not only by elevated serum T3 causing peripheral thyrotoxicosis but also brain-based hypothyroidism caused by insufficient T3 levels. Iwayama teaches that while TH analog small molecule therapies, such as DITPA, address elevated serum T3 levels, these TH analogue therapies do not correct brain T3 levels, and proposes that AAV9-MTC8 gene therapy is ideally positioned to address T3 imbalances in the brain. Thus, a person of ordinary skill in the art would have been motivated to combine AAV9-MCT8 gene therapy with traditional TH analogue therapy with a reasonable expectation of success to address both peripheral and cerebral imbalances of T3 simultaneously.
Furthermore, since the serum T3 levels are indicative of DITPA efficacy, one of ordinary skill (e.g., medical doctor) in the relevant art (i.e., medical field) to the claimed therapeutic method would readily and reasonably understand that the dose optimization of DITPA should correlate with serum T3 levels, which were known to be continuously monitored as disclosed in Verge, in order to limit known adverse effects of DITPA treatment. The two-week dose escalation regimen was disclosed by Verge, and thus the claims are simply applying a known clinically practiced dosing scheme of DITPA therapy.
It would have further been obvious to one of ordinary skill in the art to additionally include TRIAC along with DITPA in the combination therapy with AAV9-MCT8 gene therapy. Groeneweg teaches TRIAC as an additional TH analog small molecule therapy that “seems a reasonable treatment strategy to ameliorate the consequences of untreated peripheral thyrotoxicosis in patients with MCT8 deficiency” (see Summary: interpretation). Like DITPA, TRIAC is effective in the periphery. Thus, one of ordinary skill in the art would have been motivated to additionally add TRIAC along with DITPA when combining these TH analog therapies with AAV gene therapy for MCT8 deficiency with a reasonable expectation of success to achieve either an additive or even a synergistic effect for ameliorating peripheral thyrotoxicosis while simultaneously addressing the cerebral hypothyroidism of AHDS.
This is a provisional nonstatutory double patenting rejection.
Claims 1-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-8, and 16 of copending Application No. 18350116 in view of Iwayama H, et. al., (THYROID 26(9) pp 1311-1319, provided in IDS, published 23 Aug., 2016), Verge CF, et. al., (J Clin Endrocinol Metab, 97(12):4515-4523, published 19 Sept, 2012), and Groeneweg S et al. (Lancet Diabetes Endocrinology, 7:695-706, provided in IDS, published 31 July, 2019).
The copending claims are drawn to a method of treating Allan-Herndon-Dudley syndrome, the method comprising administration of 3,5-diiodothyropropionic acid (DITPA) to a subject in need thereof, wherein administration begins within three days after birth of the subject, and the administration is in a total daily dosage of at least 2 milligrams per kilogram of body weight of the subject, and, wherein the administration reduces triiodothyronine (T3) serum levels to normal, increases T3 brain levels to normal, increases to, or maintains, normal serum levels of thyroxine (T4), and decreases to, or maintains, normal thyroid stimulating hormone (TSH) serum levels. See the additional copending claims for additional limitations of the instant dependent claims.
To the extent that there are limitations of the instant claims that are not taught by the copending claims, the teachings of Iwayama, Verge, and Groeneweg are discussed above. Given the substantially similar subject matter between the copending claims and the teachings of Iwayama, Verge, and Groeneweg, it would have been obvious to have modified the subject matter of the copending claims in the manner discussed above to arrive at the instant claims for substantially the same reasons as discussed above. It was well-established in the art at the time of filing that AHDS driven by MCT8 deficiency is characterized not only by elevated serum T3 causing peripheral thyrotoxicosis but also brain-based hypothyroidism caused by insufficient T3 levels. Iwayama teaches that while TH analog small molecule therapies, such as DITPA, address elevated serum T3 levels, these TH analogue therapies do not correct brain T3 levels, and proposes that AAV9-MTC8 gene therapy is ideally positioned to address T3 imbalances in the brain. Thus, a person of ordinary skill in the art would have been motivated to combine AAV9-MCT8 gene therapy with traditional TH analogue therapy with a reasonable expectation of success to address both peripheral and cerebral imbalances of T3 simultaneously.
Furthermore, since the serum T3 levels are indicative of DITPA efficacy, one of ordinary skill (e.g., medical doctor) in the relevant art (i.e., medical field) to the claimed therapeutic method would readily and reasonably understand that the dose optimization of DITPA should correlate with serum T3 levels, which were known to be continuously monitored as disclosed in Verge, in order to limit known adverse effects of DITPA treatment. The two-week dose escalation regimen was disclosed by Verge, and thus the claims are simply applying a known clinically practiced dosing scheme of DITPA therapy.
It would have further been obvious to one of ordinary skill in the art to additionally include TRIAC along with DITPA in the combination therapy with AAV9-MCT8 gene therapy. Groeneweg teaches TRIAC as an additional TH analog small molecule therapy that “seems a reasonable treatment strategy to ameliorate the consequences of untreated peripheral thyrotoxicosis in patients with MCT8 deficiency” (see Summary: interpretation). Like DITPA, TRIAC is effective in the periphery. Thus, one of ordinary skill in the art would have been motivated to additionally add TRIAC along with DITPA when combining these TH analog therapies with AAV gene therapy for MCT8 deficiency with a reasonable expectation of success to achieve either an additive or even a synergistic effect for ameliorating peripheral thyrotoxicosis while simultaneously addressing the cerebral hypothyroidism of AHDS.
This is a provisional nonstatutory double patenting rejection.
Claims 1-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18350089 in view of Iwayama H, et. al., (THYROID 26(9) pp 1311-1319, provided in IDS, published 23 Aug., 2016), Verge CF, et. al., (J Clin Endrocinol Metab, 97(12):4515-4523, published 19 Sept, 2012), and Groeneweg S et al. (Lancet Diabetes Endocrinology, 7:695-706, provided in IDS, published 31 July, 2019).
The copending claims are drawn to A method of treating Allan-Herndon-Dudley syndrome, the method comprising determining that a prenatal subject is in need of treatment for Allan-Herndon-Dudley syndrome; and administering 3,5-diiodothyropropionic acid (DITPA) or a salt thereof to a pregnant mother of the prenatal subject, wherein administration begins no more than ten weeks after conception of the subject.
To the extent that there are limitations of the instant claims that are not taught by the copending claims, the teachings of Iwayama, Verge, and Groeneweg are discussed above. Given the substantially similar subject matter between the copending claims and the teachings of Iwayama, Verge, and Groeneweg, it would have been obvious to have modified the subject matter of the copending claims in the manner discussed above to arrive at the instant claims for substantially the same reasons as discussed above. It was well-established in the art at the time of filing that AHDS driven by MCT8 deficiency is characterized not only by elevated serum T3 causing peripheral thyrotoxicosis but also brain-based hypothyroidism caused by insufficient T3 levels. Iwayama teaches that while TH analog small molecule therapies, such as DITPA, address elevated serum T3 levels, these TH analogue therapies do not correct brain T3 levels, and proposes that AAV9-MTC8 gene therapy is ideally positioned to address T3 imbalances in the brain. Thus, a person of ordinary skill in the art would have been motivated to combine AAV9-MCT8 gene therapy with traditional TH analogue therapy with a reasonable expectation of success to address both peripheral and cerebral imbalances of T3 simultaneously.
Furthermore, since the serum T3 levels are indicative of DITPA efficacy, one of ordinary skill (e.g., medical doctor) in the relevant art (i.e., medical field) to the claimed therapeutic method would readily and reasonably understand that the dose optimization of DITPA should correlate with serum T3 levels, which were known to be continuously monitored as disclosed in Verge, in order to limit known adverse effects of DITPA treatment. The two-week dose escalation regimen was disclosed by Verge, and thus the claims are simply applying a known clinically practiced dosing scheme of DITPA therapy.
It would have further been obvious to one of ordinary skill in the art to additionally include TRIAC along with DITPA in the combination therapy with AAV9-MCT8 gene therapy. Groeneweg teaches TRIAC as an additional TH analog small molecule therapy that “seems a reasonable treatment strategy to ameliorate the consequences of untreated peripheral thyrotoxicosis in patients with MCT8 deficiency” (see Summary: interpretation). Like DITPA, TRIAC is effective in the periphery. Thus, one of ordinary skill in the art would have been motivated to additionally add TRIAC along with DITPA when combining these TH analog therapies with AAV gene therapy for MCT8 deficiency with a reasonable expectation of success to achieve either an additive or even a synergistic effect for ameliorating peripheral thyrotoxicosis while simultaneously addressing the cerebral hypothyroidism of AHDS.
This is a provisional nonstatutory double patenting rejection.
Applicant Remarks Regarding Rejections under Double Patenting
Applicant has requested for the double patenting rejections to be help in abeyance. However, the double patenting rejections can not be held in abeyance because of reasons of record and because applicant did not provide any reasons as to why the double patenting rejections are improper. Therefore, the double patenting rejections are maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/COREY LANE BRETZ/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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