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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/12/2025 has been entered.
Claims 2, 4-5, 8, 10, 13, 15-18, 21, 25, 28-33, 35, 37 and 39-40 have been canceled, claim 41 is newly added, claims 27, 34, 36 and 38 have been withdrawn from consideration as being drawn to non-elected subject matter, and claims 1, 3, 6-7, 9 11-12, 14, 19-20, 22-24, 26 and 41 have been considered on the merits. All arguments have been considered.
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.
Claim(s) 1-3, 6-7, 9, 11-12, 14, 19, 22-24 and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Harrison et al. (2013, Molecular Therapy; IDS ref.) in view of Anikster et al. (2000, Pediatric Research), Moisseiev et al. (2016, Invest. Ophthalmol. Vis. Sci.; of record) and Cherqui (WO2017/165167; of record).
Regarding claims 1-3, 6-7, 9, 12 and 19, Harrison et al. teach a method of administering autologous HSPC expressing human CTNS using SIN-LV such as pCCL-CTNS to ctns-/- mice (entire document; Materials and Methods; p.441-442). Harrison et al. teach that the HSPCs expressing a functional CTNS transgene were capable of decreasing cystine content in all tissues and improved kidney function (Abstract). They measured cystine contents tissues including eye (p.434, 2nd col., Long-term in vivo correction).
Regarding the method of treating a human subject suffering from ocular cystinosis, Harrison et al. do not particularly teach the method is for a human subject suffering from ocular cystinosis.
Anikster et al. teach that ocular non-nephropathic cystinosis is a variant of the classic nephropathic type of cystinosis and it is an autosomal recessive lysosomal storage disorder characterized by photophobia due to corneal cystine crystals but absence of renal disease (see Abstract). Anikster et al. teach that the ocular cystinosis in human patients had mutations in CTNS mRNA (Abstract).
It would have been obvious to a person skilled in the art to use the method of Harrison et al. for the ocular non-nephropathic cystinosis with a reasonable expectation of success. A person of ordinary skilled in the art would have been motivated to do so because one skilled in the art would recognize that the ocular non-nephropathic cystinosis is due to the mutation in the CTNS gene as the nephropathic cystinosis, and thus, the HSPCs expressing CTNS gene would be successfully rescue the defect in the eye of a human patient suffering from ocular non-nephropathic cystinosis. As Harrison et al. show the efficacy of animal model in treating cystinosis using HSCP expressing CTNS gene as a proof-of-concept, one skilled in the art would recognize that human trial is obvious to try based on the teaching of Harrison et al. with a reasonable expectation of success. The combined teaching of Harrison et al. in view of Anikster et al. would also meet the new limitation of claim 41 directed to the ocular cystinosis being ocular non-nephropathic cystinosis.
Regarding the step of transplanting the HSPCs into an eye of the subject or intravitreal injection (claims 1 and 11-12), it would have been obvious to a person skilled in the art to administer HSPCs expressing CTNS into an eye of the human patients suffering from ocular non-nephropathic cystinosis. This is because the symptoms of ocular non-nephropathic cystinosis (corneal cystine crystal) are limited to the eye without renal disease and thus, one skilled in the art would recognize that the HSPCs expressing CTNS gene would be reasonable to target to the eye in order to treat the symptoms in the eye with a reasonable expectation of success.
Regarding the intravitreal injection, as the intravitreal injection to the eyes of HSPCs in an attempt to treat retinal degeneration is known in the art according to Moisseiev et al. (Abstract), one skilled in the art would treat the ocular cystinosis taught by Anikster et al. by intravitreally injecting the HSPCs for the method of Harrison et al. in view of Anikster et al. with a reasonable expectation of success.
Regarding claim 9, Harrison et al. teach that the generation of CTNS expressing HSPC using viral vector, pCCL-CTNS, and the viral transduction is carried ex vivo using HSPC isolated from Ctns-/- mice (p.422, 1st col.). Thus, it would have been obvious to a person skilled in the art to use the human HSPC from the subject being treated to carry out viral transduction of pCCL-CTNS with a reasonable expectation of success.
Regarding claim 14 directed the HSPCs being CD34+ cells. While Harrison et al. do not particularly teach that the HSPCs are CD34+ cells, however, it is inherent that human HSPCs are CD34+ according to Cherqui (para. 77).
Regarding claim 19 directed to the level of cystine in the eye being reduced following [the] treatment or claims 22-23 directed to the measuring before and/or after the treatment, as discussed above, Harrison et al. teach the reduction of cystine level in various tissues including eye upon the HSPC transplantation (Fig. 3b).
Regarding claim 24, Harrison et al. teach that the level of cystine in eye is measured using serum obtained by eye bleeds (p.442, 2nd col.), and thus, meet the limitation.
Regarding claim 41 directed to the treatment comprising improved corneal thickness and structure or intraocular pressure, this wherein clause is directed to the results of the claimed method rather than providing any additional active step required for the claimed method. As the method of Harrison et al. in view of Anikster et al., Moisseiev et al. and Cherqui is considered identical to the claimed method, the same results are expected from the combined teachings.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim(s) 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Harrison et al. in view of Anikster et al., Moisseiev et al. and Cherqui as applied to claims 1-3, 6-7, 9, 11-12, 14, 19, 22-24 and 41 above, and further in view of Eddy et al. (US2014/0275279) and Ur et al. (2013, Molecular Therapy; Abstract #494).
Regarding claim 20 directed to the subject having been on cysteamine therapy, the cited references do not teach the limitation.
Eddy et al. teach that cysteamine therapy is to reduce the symptoms caused by cystinosin deficiency in Ctns-/- mice (Examples 9-10).
Ur et al. teach treatment is available for treating cystinosis with the drug cysteamine to reduce intracellular cystine content (Abstract).
Thus, it would have been obvious to a person skilled in the art to use the ctns-/- mice that have been treated with cysteamine for the method of Harrison et al. with a reasonable expectation of success. This is because the treatment of Ctns-/- mice with cysteamine is known in the art according to Eddy et al., and Ur et al. teach that the limit of cysteamine therapy in treating cystinosis is only delaying the progression of the disease, and suggest the HSPC gene therapy using HSPC expressing the functional CTNS gene for treating cystinosis (Abstract). Thus, one skilled in the art would recognize that the method of Harris et al. can be used for the Ctns-/- mice that have been treated with cysteamine.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim(s) 26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Harrison et al. in view of Anikster et al., Moisseiev et al. and Cherqui as applied to claims 1-3, 6-7, 9, 11-12, 14, 19, 22-24 and 41 above, and further in view of Simpson et al. (2011, Mol. Vis.; IDS ref.)
Regarding claim 26 directed to cystine crystals being measured by in vivo confocal microscopy, Harrison et al. in view of Anikster et al., Moisseiev et al. and Cherqui do not particularly teach the limitation.
Simpson et al. teach a method of quantitative analysis of cystine crystals in the Ctns-/- mice using in vivo confocal microscopy (see entire document).
It would have been obvious to a person skilled in the art to use the in vivo confocal microscopy taught by Simpson et al. for the method of Harrison et al. in view of Anikster et al., Moisseiev et al. and Cherqui with a reasonable expectation of success.
A person of ordinary skilled in the art would have been motivated to use in vivo confocal as it is known technique in the art for the measurement of cystine crystals, and the purpose of Harrison’s method is to reduce the cystine crystals caused by the deficiency of CTNS and the reduction of the crystals. Thus, one skilled in the art would choose the in vivo confocal microscopy to determine the effectiveness of the method taught by Harrison et al. in view of Anikster et al., Moisseiev et al. and Cherqui.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Arguments
Applicant’s arguments with respect to the claim rejection under 112(a) have been fully considered and are persuasive in view of the instant amendment. Thus, the rejections have been withdrawn.
Applicant's arguments filed 11/12/2025 have been fully considered but they are not persuasive.
Regarding claim rejection under 103, applicant argued that the Examiner has failed to establish a prima facie case of obviousness because the references fail to teach or suggest each and every element of the amended claims, and the Examiner has failed to provide evidence that one skilled in the art would have any reasonable expectation of successfully treating ocular cystinosis by administering an HSPC modified to express a functional CTNS directly to the eye of a subject.
The Examiner respectfully disagrees with this argument. It is noted that the claim rejection presented above has cited additional reference to address ocular non-nephropathic cystinosis (Anikster et al.). The claim rejection above has fully addressed the claimed invention and provides sufficient rationale to combine the teachings of the cited references with a reasonable expectation of success as discussed below.
Applicant argued that Harrison is directed to the systemic administration of an HSPC expressing CTNS and they do not teach the transplanting into the eye of a subject as acknowledged by the 103 rejection. Applicant argued that Moisseiev does not teach any expression of therapeutic proteins, gene therapy or the challenges of expression of such proteins in cells administered to the eyes of subject. Applicant alleged that the combination of Harrison with Moisseiev is based on the impermissible hindsight.
It has been acknowledged that Harrison et al. do not teach the transplanting of HSPCs into the eye of the subject, however, they do teach that the systemic administration of HSPCs expressing CTNS transgene resulted in the reduction of cystine level in various organs affected by the disease including eye (see Fig. 3b). Thus, the teaching of Harrison et al. indicates that HSPCs expressing functional CTNS gene would be effective when administered intravenously. One skilled in the art would recognize that as the intravenous administration of HSPCs expressing CTNS gene is capable of reducing cystine content in eye, the HSPCs expressing CTNS gene can be locally administered to the affected organs including eye. Thus, it would have been obvious to a person skilled in the art to administer the HSPCs expressing CTNS gene taught by Harrison et al. into the eye to reduce the cystine level.
Furthermore, Anikster et al. (newly cited in the claim rejection above) teach ocular non-nephropathic cystinosis which is only affected in eye and this variant of cystinosis is confined to eye without renal disease. Thus, for ocular cystinosis that is confined to eye, one skilled in the art would consider intracameral or intravitreal injection into the eye would be a more targeted alternative to the intravenous systemic administration. Thus, it is concluded that one skilled in the art would expect the intravitreal or intracameral delivery of HSCP expressing CTNS gene would be able to treat the ocular cystinosis in the absence of evidence to the contrary.
Applicant alleged that administration of the claimed HSPCs demonstrated surprising and unexpected efficacy that could not have been expected based on any reasonable interpretation of the prior art. Applicant stated that high engraftment of HSPCs having been introduced a polynucleotide encoding a functional human (CTNS) protein almost complete resolution of crystals form the epithelial layer to the middle stroma referring paragraph [0096]. The paragraph [0096] does not provide any basis to consider the long-term effect of HSC transplantation in Ctns-/- mice or this alleged effect is solely based on intravitreal or intracameral injection compared to systemic, intravenous injection taught by Harrison et al.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Based on the above discussion, it is the Examiner’s position that the combined teachings of the cited references render the claimed invention obvious.
Conclusion
No claims are allowed.
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/TAEYOON KIM/Primary Examiner, Art Unit 1631