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 .
Amendments
In the reply filed 10/30/2025, Applicant has amended Claims 1-3, 8-10, 13-14, 17, 20-21, cancelled claims 4 and 12, and added new claims, Claims 22-29.
Claims 1-3, 5, 7-11, 13-29 are under consideration.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/30/2025 was filed after the mailing date of the non-final Office action on 7/01/2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objections to the Specification
The prior objection to the disclosure because it contained an embedded hyperlink and/or other form of browser-executable code is withdrawn
Withdrawn Objections to the Drawings for
Sequence Compliance
The prior objections to Figure 2 and Figure 5 of the Specification as not conforming to sequence rules, requiring the use of “SEQ ID NO:” is withdrawn in light of the amendments to the specification indicating the SEQ ID NOs.
Withdrawn Claim Objections
The objection to Claim 17 has been withdrawn due to applicant’s amendment to define “CB7”.
Withdrawn 35 USC § 112
The prior rejections of Claims 1-3, 5, 7-11 and 19 under 35 U.S.C. § 112(b) pre-AIA 2nd paragraph as being indefinite is withdrawn in light of Applicant’s amendments of Claim 1 to clarify the administration step, amend the dosing table with upper and lower limits, and clarify the term “dose”.
Withdrawn 35 USC § 101
The prior rejection of Claims 1-3, 5, 7-11, 15-21 under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more is withdrawn in light of Applicant’s amendment of Claim 1 to include step of administration at a specific set of doses, which adds significant more to the claimed invention.
Withdrawn 35 USC § 103
The prior rejection of Claims 1-3, 5, 7-11, 13-21 under 35 U.S.C. 103 as being unpatentable over Hinderer et al. (US 2019/0038772, filed 2/02/2017, published 2/07/2019, see IDS filed 1/25/2023), in view of Park et al., (Rad Protect Dosimetry, 2006, 118:275-279) is withdrawn in light of Applicant’s amendment of independent Claims 1, 20 and 21 to no longer require a MRI step for determining brain mass, and to clarify the upper limit of the dosing table that has been incorporated into the independent claims.
New Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(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, 2, 5, 7-11, 13, 15-16, 18-21, 26-29 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Yoo et al., (WO2018/144441, filed 1/30/2018, published 8/09/2018, see IDS filed 1/25/2023).
In regard to claims 1, 20, and 21, Yoo teaches a method for treating a human subject diagnosed with MPS comprising delivering a therapeutically effective amount of a recombinant IDUA enzyme produced by the human subject’s neuronal cells transduced with a rAAV9-hIDUA expression vector [0002, 0011, 0132, 0178, 0193].
In regard to the dose determination and dosing tables of claims 1, 20 and 21, Yoo teaches that a single flat dose of 1.3 x1013 gc is administered to an adult patient [0132]. Yoo teaches that this single flat dose is determined based the human subject’s brain mass with a dosing factor of 1 x1010 gc/gram brain mass Example 6 [0178], Example 7 [0193], Example 8 [0207]. Thus, the brain mass of the adult patients of Yoo would have been 1,300 grams as per the dosing tables of claims 1, 20, and 21.
In regard to claims 2, 5, 28 and 29, Yoo teaches intracisternal administration [0178, 0193, 0207].
In regard to claim 7, Yoo teaches administering the vector in a volume of about 5 ml [0178, 0193, 0207], which would not exceed 10% of the CSF volume of an adult at over 100 ml.
In regard to claims 8-10, Yoo teaches administering immunosuppressive therapy of tacrolimus, sirolimus (rapamycin), and corticosteroids prior to gene therapy to prevent immune responses to the transgene and/or AAV vector that is withdrawn by week 48 (Example 7 [0191], Example 8 [0205]), which is after 180 days.
In regard to claim 11, Yoo teaches the human IDUA expression cassette is used [0177], and discloses the 653 amino acid sequence of SEQ ID NO: 1 (Fig. 1, [0067]), which is 100% identical to instant SEQ ID NO: 1.
In regard to claim 13, as stated supra, Yoo teaches that 1.3 X 1013 total gc are delivered to an adult with a brain mass over 1,201 grams.
In regard to claims 15, 16, 26 and 27, as stated supra, Yoo teaches recombinant AAV9 vector is administered.
In regard to claim 18, as stated supra, Yoo teaches a single administration [0178, 0193, 0207].
In regard to claim 19, as stated supra, Yoo teaches an adult human patient, which is older than 4 months of age.
Accordingly, Yoo anticipates instant claims.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 10/30/2025 are acknowledged.
Applicant argues that the cited prior art of Hinderer does not teach or suggest the claimed Dose 1 or Dose 2, wherein the doses are determined according the range of brain mass as set forth in the claimed tables.
Moreover, Applicant argues that compared to the specific brain mass-based method disclosed by the prior art, the claimed tables allow the subject to receive a personalized brain mass range-based dose, wherein subjects having brain masses falling into the same range receive a flat fixed dose. The additional benefits of the dosing table with a fixed flat dose is to reduce medical errors and the time required for dose calculation and preparation, and drug administration efficiency is improved.
Applicant's arguments have been fully considered but they are not persuasive.
In response to Applicant's argument, as stated in the revised rejection based on Applicant’s amendment of the dosing table to include no upper limit, the flat dose of 1.3 x 1013 for an adult brain of at least 1,201 grams is clearly anticipated.
Furthermore, any potential benefits of a flat dose based on a personalized dose determined by a brain mass range are minimal in the adult patient with the claimed range of 1201 grams to “no upper limit”. This weight range for adult brains was well known in the prior art (as evidenced by Dekaban et al. 1978), and as stated above, the flat dose of Yoo anticipates the claimed Dose 1 and makes obvious Dose 2 from the table with no upper weight limit for adult brains, and would therefor naturally possess of the benefits associated with dose determination, preparation, and efficiency of administration.
Claim Rejections - 35 USC § 103
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Yoo et al., (WO2018/144441, filed 1/30/2018, published 8/09/2018, see IDS filed 1/25/2023), as evidenced by Dekaban et al. (Ann Neurol, 1978, 4:345-356).
Yoo teaches a method for treating a human subject with MPS1 gene therapy comprising the administration of MPS1 gene therapy at a dose in terms of GC per brain mass.
Specifically in regard to the Dose2 of claim 14, Yoo teaches a dose in terms of GC per brain mass of 5 x1010 gc/gram of brain mass [0133] (Note that Applicant’s originally filed dosing table indicated that 5 x1010 gc/gram of brain mass corresponded to “Dose 2”).
Furthermore, in regard to claim 14, Yoo teaches a flat dose range of 1.4 x1013 to 7.0 x1013 gc that is administered to an adult patient [0132], which encompasses the flat dose 6.5 x1013 administered to an adult brain weight of 1.3 kg when using Yoo’s dosing equation of 5 x1010 gc/gram of brain mass.
Finally, Dekaban evidences that the average mass of an adult female brain is about 1.3 kg (p.349, Table 3).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to practice a method of treating MPS I in an adult human subject by administering the rAAV-hIDUA vector a flat dose range of 1.4 x1013 to 7.0 x1013 gc based on a dosing equation of 5 x1010 gc/gram of brain mass as taught by Yoo, and choose the flat dose of 6.5 x1013 gc in an adult female MPSI patient with an average brain mass of 1.3 kg with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so because in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 10/30/2025 are acknowledged and have been addressed above.
Claims 3 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Yoo et al., (WO2018/144441, filed 1/30/2018, published 8/09/2018, see IDS filed 1/25/2023), in view of Park et al., (Rad Protect Dosimetry, 2006, 118:275-279, prior art of record)
Yoo teaches a method for treating a human subject with MPS1 gene therapy comprising the administration of MPS1 gene therapy at a dose in terms of GC per brain mass.
However in regard to claims 3 and 22, although Yoo teaches the patients treated should not have a contraindication for MRI (Example 6 [0166], Example 7 [0183], Example 8 [0198]), they are silent with respect to using MRI to determine the brain mass so as to calculate the dose.
In regard to claims 3 and 22, Park teaches the method step of determining the brain mass of a human subject by measuring the brain volume with MRI and multiplying by the density of brain tissue (i.e., about 1.03 g/cm3) (p. 276-277, Materials and Methods, and see Table 2).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to practice a method of treating MPS I in a human subject with no contraindication for MRI at a dose of vector in terms of GC/brain mass as taught by Yoo, and combine the step of determining the brain mass by MRI as taught by Park with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Park because brain mass estimates used by Yoo appear to be based on the age of an unspecified reference subject with no accounting for individual differences across ethnic populations, while Park teaches that in order to conduct consisting dosing (albeit for radiotherapy), it is crucial to establish reference data (as per brain mass) for specific ethnic populations (Introduction). Thus, it would have been predictably obvious to use MRI to determine the subject’s brain mass in order to achieve a more accurate dose of vector in gc/brain mass for different ethnic population with MPS I.
In regard to claim 3, as stated supra, Park teaches multiplying MRI volumetric data with a brain density of 1.03 g/cm3. Although, Park is silent to a brain density of 1.046 g/cm3, it is close enough to the prior art that one skilled in the art would have expected them to have the same therapeutic properties. In other words, absence evidence to the contrary, a 1/100th difference in dosing of the AAV vector would have been expected to achieve the same treatment result.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 10/30/2025 are acknowledged and have been addressed above.
Claims 17, and 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over Yoo et al., (WO2018/144441, filed 1/30/2018, published 8/09/2018, see IDS filed 1/25/2023), in view of Hinderer et al. (US 2019/0038772, filed 2/02/2017, published 2/07/2019, see IDS filed 1/25/2023)
Yoo teaches a method for treating a human subject with MPS1 gene therapy comprising the administration of an rAAV9-hIUDA gene therapy vector at a dose in terms of GC per brain mass.
In regard to claims 17 and 23-25, Yoo suggests the rAAV vector comprise CB7 promoter in order to express the IDUA transgene in neurons and glial cells [0010, 0033, 0103].
Furthermore, in regard to claims 23-25, Yoo suggests the rAAV is flanked by ITRs, comprises a TATA box in the promoter, a chicken beta-acting intron, a codon optimized transgene, and a rabbit beta-globin polyA [0085, 0094, 0103], they are silent to the nucleic acid sequence of this rAAV construct.
In regard to claims 23, 24 and 25, Hinder teaches recombinant vector for MPS1 gene therapy is the “CB7.CI.hIDUAco.RBG” construct that is flanked by ITRs, comprises a TATA box in the CB7 promoter, a chicken beta-acting intron, a codon optimized hIDUA transgene, and a rabbit beta-globin polyA that corresponds to SEQ ID NO:3 ([0330], pgs. 50-53, see also Figs. 1 & 11 of Hinder), and is 100% identical to instant SEQ ID NO:27 (see SCORE search 1/15/2026, rnpm.file, result #1).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 10/30/2025 are acknowledged and have been addressed above.
Conclusion
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 extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ARTHUR S LEONARD whose telephone number is (571)270-3073. The examiner can normally be reached on Mon-Fri 9am-5pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Doug Schultz can be reached on 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ARTHUR S LEONARD/Examiner, Art Unit 1631