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.
Information Disclosure Statement
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.
The instant case, as of this office action, contains three IDS files, which comprise a total of 31 non-patent literature references. However, the specification contains two lists of reference, taken together comprise a total of 130 non-patent references. See reference lists beginning on page 16 (containing 53 references) and page 36 (containing 77 references).
Specification
The disclosure is objected to because of the following informalities: section headings are not consistent with 37 CFR 1.77(b).
Appropriate correction is required. These guidelines are suggested for the applicant' s use:
Arrangement of the Specification
As provided in 37 CFR 1.77(b), the specification of a utility application should include the following sections in order. Each of the lettered items should appear in upper case, without underlining or bold type, as a section heading. If no text follows the section heading, the phrase “Not Applicable” should follow the section heading:
(a) TITLE OF THE INVENTION.
(b) CROSS-REFERENCE TO RELATED APPLICATIONS.
(c) STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT.
(d) THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT.
(e) INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A READ-ONLY OPTICAL DISC, AS A TEXT FILE OR AN XML FILE VIA THE PATENT ELECTRONIC SYSTEM.
(f) STATEMENT REGARDING PRIOR DISCLOSURES BY THE INVENTOR OR A JOINT INVENTOR.
(g) BACKGROUND OF THE INVENTION.
(1) Field of the Invention.
(2) Description of Related Art including information disclosed under 37 CFR 1.97 and 1.98.
(h) BRIEF SUMMARY OF THE INVENTION.
(i) BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S).
(j) DETAILED DESCRIPTION OF THE INVENTION.
(k) CLAIM OR CLAIMS (commencing on a separate sheet).
(l) ABSTRACT OF THE DISCLOSURE (commencing on a separate sheet).
(m) SEQUENCE LISTING. (See MPEP § 2422.03 and 37 CFR 1.821 - 1.825). A “Sequence Listing” is required on paper if the application discloses a nucleotide or amino acid sequence as defined in 37 CFR 1.821(a) and if the required “Sequence Listing” is not submitted as an electronic document either on read-only optical disc or as a text file via the patent electronic system.
The disclosure is objected to because it contains multiple instances of embedded hyperlinks and/or other form of browser-executable code. Applicant is required to locate each instance and delete the embedded hyperlinks 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 below for instances of embedded hyperlinks:
Pg. 20, reference 38.
Pg. 37, reference 15.
Pg. 37, reference 16.
Claim Objections
Claim 1 is objected to because of the following informalities: “administering gene therapy” and “introduce normal human MCT8” lack proper antecedent basis. The examiner has determined that these are not aggravated situations where the lack of antecedent basis makes the scope of the claim indeterminate. Appropriate correction is required. Applicant may remedy by amendment to the claims; for example, reciting “administering a gene therapy” and “introduce a normal (wild-type) human MCT8.”
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 1-11 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 instant application claims “administrating gene therapy to introduce normal human MCT8 into a subject.” However, the specification does not provide adequate written description support for the entire genus of “normal human MCT8.”
The specification does not disclose a SEQ ID NO, a specific nucleotide sequence, or define structural limitations that characterize the claimed “normal human MCT8” transgene. Nor does the specification define which isoform, splice variant, or allelic variant of MCT8 is encompassed by the claims. As presently drafted, the claim language “normal human MCT8” encompasses multiple distinct isoforms and potential variants.
The prior art demonstrates that multiple isoforms of human MCT8 exist. For example, Iwayama (THYROID 26(9) pp 1311-1319, provided in IDS, published 23 Aug., 2016) discloses both a full-length isoform (LhMCT8) and a short isoform (ShMCT8) of “normal human MCT8.” However, the two isoforms taught by Iwayama are not functionally equivalent as transgenes in AAV vectors. Iwayama reports “the AAV-9 containing the full-length cDNA, LhMCT8, was also transcribed and translated in the brain following IV injection (Fig. 2A, right panel, and Fig. 2B, lanes 8 and 9). However, due to its clear toxicity, a decision was made to focus on the ShMCT8 isoform for further evaluation of the protein distribution and function.” (see results: Viral delivery of hMCT8 leads to hMCT8 mRNA and protein in the brain). These teachings demonstrate that different “normal human MCT8” isoforms may have materially different safety and functional profiles; for instance, “functional profiles” pertaining to the claimed “gene therapy” function that is claimed “to increase T3 in the subject’s brain and induce a T3-mediated response.” Hence, the required structure-function correlation for the entire genus of “normal human MCT8” was not known in the prior art, nor does the instant specification describes such correlation for the entire genus encompassing a myriad of structural variants.
Therefore, because the claims read on both full-length and short isoforms, as well as any other naturally occurring or engineered variant that could be considered “normal human MCT8,” the claims recite a genus of transgenes without identifying a representative number of species or structural features common to the genus.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4 and 8-9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liao XH, et. al, (THYROID 32(7) pp 849-859, provided in IDS, published online 8 July, 2022 with a preprint version of this study posted on BioRxiv, 2 Nov., 2021).
Regarding claim 1, Liao teaches a method of treating Allan-Herndon-Dudley syndrome (abstract: “IV administration of AAV9, carrying the human MCT8, to juvenile dKO mice manifesting AHDS has long-term beneficial effects, predominantly on the CNS,”) the method comprising determining that a subject is in need of treatment for Allan-Herndon-Dudley syndrome (abstract: “was tested in the well-established Mct8-/y/Organic anion-transporting polypeptide 1c1 (Oatp1c1)-/- double knockout (dKO) mouse model of AHDS, which, unlike Mct8-/y mice, displays both neurological and TH phenotype.”); 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 (abstract: “the potential of IV delivery of AAV9 carrying human MCT8 was tested,” and resulted in “improved locomotor and cognitive functions at P120–P140, which was accompanied by a near normalization of T3 content and an increased response of positively regulated TH-dependent gene expression in different brain regions examined (thalamus, hippocampus, and parietal cortex).”).
Regarding claim 2, Liao teaches the normal human MCT8 is introduced using a viral vector AAV9 (abstract: “the potential of IV delivery of AAV9 carrying human MCT8 was tested”).
Regarding claims 3-4 and 8-9, Liao teaches further “administration of DITPA to the subject” and/or “administration of TRIAC to the subject” who received the gene therapy containing normal human MCT8 either by AAV9 or not (discussion: In patients with AHDS, the TH analogues, DITPA and TRIAC, reduced the high serum T3 concentrations; however, there was no evidence for improvement in neurological symptoms. Thus, TH analogs can be considered to be used in combination with gene therapy.”). Liao further teaches that “although AAV9-MCT8 treatment did not significantly alter serum levels of TSH, T4, T3, rT3, and T3/T4 ratio, the combination of a slight reduction in T3 and an increase in rT3 resulted in a significant decrease of the T3/rT3 ratio in agreement with the observed attenuation of Dio1 expression. This indicates that AAV9-MCT8 delivery at a juvenile stage can partially improve the abnormalities in serum” (see results)
Claims 1-2 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Iwayama H, et. al., (THYROID 26(9) pp 1311-1319, provided in IDS, published 23 Aug., 2016).
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”).
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”).
Note: the Mct8 knockout and dKO mouse models described in Liao and Iwayama are well-established animal models of Allan-Herndon-Dudley syndrome and exhibit the neurological and thyroid hormone abnormalities characteristic of the disorder; thus, these subjects are determined to be in need of treatment for AHDS prior to administering the disclosed gene therapy.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 Liao XH, et. al, (THYROID 32(7) pp 849-859, provided in IDS, published online 8 July, 2022 with a preprint version of this study posted on BioRxiv, 2 Nov., 2021) in view of Verge CF, et. al., (J Clin Endrocinol Metab, 97(12):4515-4523, provided in IDS, published 19 Sept, 2012).
Teachings of Liao regarding claims 1-4 and 8-9 are incorporated herein by reference to the relevant 102 rejection above.
Liao does not teach 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 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).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to administer DITPA in the escalating dosing regimen of one dose for two weeks and continuing for at least two weeks at a higher dose, as taught by Verge, in combination with the MCT8 gene therapy taught by Liao. Liao teaches that IV administration of AAV9-MCT8 normalizes brain T3 content and improves neurological function; however, Liao further demonstrates that gene therapy produces limited correction of elevated serum T3 levels. Thus, while gene therapy addresses central thyroid hormone deficiency, peripheral thyrotoxicosis characterized by elevated serum T3 remains inadequately corrected. Verge teaches that DITPA reduces elevated serum T3 levels in subjects with MCT8 deficiency and provides an incremental dosing regimen administered in two-week intervals at increasing dose levels. Because Liao identifies incomplete normalization of serum T3 as a remaining biochemical abnormality following gene therapy, and suggests that the TH analogs, DITPA and TRIAC, reduce serum T3 levels and may be combined with gene therapy, a person of ordinary skill in the art would have been motivated to combine MCT8 gene therapy with DITPA +/- TRIAC to address persistent peripheral hyperthyroidism.
Furthermore, given that serum T3 elevation is the therapeutic target of DITPA treatment, it would have been obvious to determine appropriate initial and subsequent dose levels bases on measured serum T3 concentrations in order to achieve the desired therapeutic outcome with limiting adverse effects. 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 adverse effects of DITPA treatment.
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). .
Teachings of Iwayama regarding claims 1-2 are incorporated herein by reference to the relevant 102 rejection above.
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 administer 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, as taught by Verge, in combination with the MCT8 gene therapy of Iwayama.
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.
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.
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.
Conclusion
No claims are allowable.
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/COREY LANE BRETZ/ Patent Examiner, Art Unit 1635
/DANA H SHIN/Primary Examiner, Art Unit 1635