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 .
Election/Restrictions
Applicant's election with traverse of SEQ ID NO:2 in the reply filed on April 10, 2026 is acknowledged. The traversal is on the ground(s) that there is “ease of searching the species” and “not so serious” burden for all recited SEQ ID NOs as the search results of one species “will likely overlap” with others. This is not found persuasive because the burden of searching and examining all five different sequences would be serious because all recited SEQ ID NOs do not share the same sequence, and furthermore, the examination of each of all recited SEQ ID NOs in relation to the claimed “method of treating” imposes a serious burden on the examiner if restriction/election was not required.
The requirement is still deemed proper and is therefore made FINAL.
Status of Application/Amendment/Claims
This Office action is in response to the communications filed on January 30, 2026 and April 10, 2026.
Currently, claims 41-59 are pending and under examination on the merits in the instant application.
The following rejections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
Response to Arguments and Amendments
Withdrawn Rejections
Any rejections/objections not repeated in this Office action are hereby withdrawn.
New Rejections Necessitated by Amendment
Claims 41, 49, and 55 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination of process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP §706.03(y).
The Markush grouping of SEQ ID NOs:2 and 5-9 is improper because the alternatives defined by the Markush grouping do not all share a common nucleotide sequence. For instance, applicant’s elected SEQ ID NO:2 shares only about 63% nucleotide similarity with SEQ ID NO:5 with no core sequence shared between the two SEQ ID NOs.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternatives within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 41-59 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 41-59 recite “a MMACHC polynucleotide comprising the sequence of SEQ ID NO: 2, 5, 6, 7, 8, or 9” or “homocystinurina (MMACHC) polynucleotide comprising the sequence of SEQ ID NO: 2, 5, 6, 7, 8, or 9”. It is noted that SEQ ID NO:6 is an AAV.rh10 vector containing “the wild-type mouse Mmachc” sequence. See paragraph 0103 of the specification. As such, the instant claims recite structurally conflicting limitations (human MMACHC polynucleotide vs. mouse Mmachc polynucleotide), thereby rendering the claims indefinite.
Claims 46-48, 52-54, and 57-59 recite that the human MMACHC polynucleotide comprising SEQ ID NO:5, 7, 8, or 9 is administered using a viral vector that is an AAV vector “pseudotyped with rh10, type 9, type 8, or 7m8 capsid.” It is noted that all of the aforementioned SEQ ID NOs contain AAV9 as evidenced by paragraph 0103 of the specification. Hence, claims 46-48, 52-54, and 57-59 simultaneously recite the broad limitation (e.g., “viral vector”, “AAV” vector) as well as a narrower limitation (AAV9) that is inherently present in SEQ ID NOs:5 and 7-9, thereby rendering the claimed structure indefinite. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claims, and therefore not required, or (b) a required feature of the claims.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 46-48, 52-54, and 57-59 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 46-48, 52-54, and 57-59 recite that the human MMACHC polynucleotide comprising SEQ ID NO:5, 7, 8, or 9 is administered using a viral vector that is an AAV vector “pseudotyped with rh10, type 9, type 8, or 7m8 capsid.” It is noted that all of the aforementioned SEQ ID NOs contain AAV9 as evidenced by paragraph 0103 of the specification. Hence, the broad limitations (e.g., “viral vector”, “AAV” vector) fail to further limit the aforementioned SEQ ID NOs. Furthermore, the recitation of “rh10”, “type 8”, and “7m8 capsid” also fails to include the aforementioned SEQ ID NOs, which contain “type 9”.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 41-59 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 claims are drawn to a method of treating a subject having conditions associated with MMACHC protein low levels or deficiency comprising administering by any route of administration a polynucleotide sequence of SEQ ID NO:2, 5, 6, 7, 8, or 9, wherein the conditions include a wide array of various diseases/conditions. It is further noted that the instant claims encompass a treatment method comprising administering a human MMACHC protein-encoding sequence, which includes SEQ ID NOs:5-6, which contain a wild-type human MMACHC sequence and a wild-type mouse Mmachc sequence, respectively, wherein the treatment method reads on treating a human patient.
The state of the prior art pertaining to treating a human subject using a mouse sequence (e.g., SEQ ID NO:6) was non-existent. Regarding using a wild-type human DNA sequence for gene therapy such as SEQ ID NO:5 claimed in the instant case, it was known in the art that the in vivo protein expression encoded by the wild-type, non-codon-optimized nucleotide sequence is substantially low, thereby providing a suboptimal in vivo effect compared to codon-optimized nucleotide sequence. That is, the functionality/activity of a codon-optimized nucleic acid has long been known to significantly differ from an unmodified, wild-type, native nucleic acid. See for instance Urbatsch (US 2013/0011909 A1) demonstrating the drastically different in vivo biological activity in relative growth of S. cerevisiae with a statistical significance between the wild-type P-glycoprotein sequence (“WT-Pgp”) and the codon-optimized sequence (“Opti-Pgp”) in the presence of FK506 as shown in Figure 4C reproduced below.
PNG
media_image1.png
308
490
media_image1.png
Greyscale
See also Chou et al. (US 2016/0376608 A1) demonstrating the in vivo hepatic activity of the codon-optimized G6Pase (“GPE-co-G6Pase”) is different with a statistical significance compared to that of the unmodified G6Pase (“GPE-G6Pase”) as shown in Figure 11.
It is noted that the instant specification at best discloses SEQ ID NO:2, which a codon-optimized human MMACHC DNA sequence that provides extended survival of the mouse model of cblC deficiency displaying “eye pathology” and “cblC-related biochemical perturbations” when SEQ ID NO:2 is administered via an intrahepatic route. The function/activity provided by SEQ ID NO:2 cannot be extrapolated to other polynucleotide sequences that are not codon-optimized (SEQ ID NO:5). In addition, the extended survival of the mice treated with SEQ ID NO:2 is far from representing the treatment/prevention of various clinical symptoms of all of the recited conditions: methylmalonic acidemia, hyperhomocysteinemia, homocystinura, cobalamin C type and deficiency of MMACHC, low levels of MMACHC, congenital heart defects, neural tube defects, combined methylmalonic acidemia and homocystinuria X type, HCFC1 spectrum defects, hyperhomocystinuria, and vitamin B12 deficiency. Similarly, the intrahepatic administration (or direct liver delivery) of the AAV9 comprising a CBA promoter operably linked to SEQ ID NO:2 is not representative of the entire genus of “administering” that encompasses any type of delivery routes and any type of delivery vectors.
In view of the relevant prior art knowledge that the actual biological activity of a polynucleotide encoding a protein significantly differs depending on the actual polynucleotide sequence encoding the protein as evidenced by the teachings of Urbatsch and Chou, one of ordinary skill in the art would reasonably conclude that the instant specification’s disclosure of the single species of SEQ ID NO:2 that is intrahepatically administered via an AAV9 vector comprising a CBA promoter with a resultant effect of an extended survival of a treated subject is insufficient to describe the entire genus of the instantly claimed treatment method in view of the art-recognized unpredictability in biological activity/function that is highly dependent on the actual nucleotide sequence as evidenced by the teachings of Urbatsch and Chou.
In view of the foregoing, it is concluded that the instant specification fails to adequately and sufficiently describe claims 41-59 as broadly claimed and the specification fails to reasonably convey that the instant co-inventors had possession of therapeutically effective human MMACHC DNA sequences other than SEQ ID NO:2 as of the filing date sought in the instant case.
Response to Arguments
Applicant's arguments filed on January 30, 2026 have been fully considered but they are not persuasive. Applicant argues that the new claims comply with the written description requirement by pointing out paragraphs 0022, 0064-0065, 0103, and 0109 of the specification. In response, it is noted that the instant specification including the passages pointed out by applicant fails to adequately describe the entire genus of claims 41-59 for the reasons stated above in the rejection.
Conclusion
No claim is 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANA H SHIN whose telephone number is (571)272-8008. The examiner can normally be reached Monday-Thursday: 8am - 6:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, RAM SHUKLA can be reached at 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DANA H SHIN/Primary Examiner, Art Unit 1635
Prosecution Insights