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 .
Applicant’s amendment and response filed on 6/15/2026 has been received and entered into the case.
Claims 2, 4-5, 8, 10, 13, 15-18, 21, 25, 28-33, 35, 37 and 39-40 have been canceled, claims 27, 34, 36 and 38 have been withdrawn from consideration as being drawn to non-elected subject matter, and claims 1, 3, 6-7, 9 11-12, 14, 19-20, 22-24, 26 and 41 have been considered on the merits.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 (maintained)
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 filed 6/15/2026 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.
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. This deficiency has been acknowledged in the 103 rejection as above. The deficiency was addressed based on the rationale that one skilled in the art would recognize that the symptoms of ocular non-nephropathic cystinosis are limited to the eye without renal disease according to Anikster et al. and thus, one skilled in the art would try to deliver the HSPCs expressing CTNS gene to the eye. As the transplantation of HSPCs via intravitreal injection is known in the art according to Moisseiev et al., it is reasonably expected that the injection of HSPCs expressing CTNS gene would be successful. As systemic administration of HSPCs expressing CTNS as taught by Harrison, it is also expected that the intravitreal delivery of CTNS expressing HSPCs would be also successful to correct the CTNS deficiency in the subject in the absence of any evidence to the contrary.
The obviousness rejection does not require absolute predictability of success, rather it requires a reasonable expectation of success with some degree of predictability (MPEP2143.02). As discussed above, a systemic administration of CTNS-expressing HSPCs is capable of treat the CTNS deficiency, and HSPCs can be administered to the eye, and the symptoms of ocular cystinosis is limited to the eye, there is a reasonable expectation of success to administer CTNS expressing HSPCs to treat ocular cystinosis.
Thus, the applicant’s argument that a reasonable expectation of success has not been established is not persuasive.
Applicant alleged that there are specific outcome from the CTNS-modified HSPCs administered intracameral or intravitreal injection, and the prior art do not demonstrate or suggest the outcome. The alleged outcome includes (a) survive and engraft in the ocular environment; (b) differentiate into macrophages within the cornea; (c) form tunneling nanotubes capable of transferring cystinosin-bearing lysosomes to diseased corneal cells; or (d) achieve reduction of corneal cystine crystals and improvement of corneal thickness, structure, or intraocular pressure. First, these outcomes are not claimed in the instant invention. Second, even if these results are disclosed in the instant claims, however, the results of the claimed active steps would be considered inherent as the combined teachings of the cited references teach the identical steps of administering CTNS-expressing HSPCs into the eye.
The discovery of a new use for an old structure based on unknown properties of the structure might be patentable to the discoverer as a process of using. In re Hack, 245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978) and In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966). See M.P.E.P. § 2112.02.
Applicant asserted that no reference teaches isolating HSPCs from blood or bone marrow of a human subject suffering from ocular cystinosis required by claim 12. The examiner respectfully disagrees with the assertion. The claim rejection clearly stated that the “autologous” HSPCs are taught by Harrison et al. Furthermore, Harrison et al. teach the use of hematopoietic stem and progenitor cells (HSPC) are derived from bone marrow as the transduced bone marrow-derived cells of Harrison et al. are considered as HSPCs as Harrison et al. disclose CTNSeGFP-DsRed-HSPC mice that are transplanted with DsRed Ctns-/- HSPC transduced with pCCL-CTNSeGFP (p.439). This teaching meets that the HSPCs are autologous and derived from bone marrow.
While Harrison et al. teach a mouse model and the subject being treated is not human subjects as claimed. However, the claim rejection has addressed the human subjects based on the teaching of Anikster et al. which teaches a method of treating human subject having ocular cystinosis. Considering the teaching of Harrison et al. with regard to the autologous bone marrow derived HSPCs in ctns-/- mice, it would have been obvious to a person skilled in the art to use human HSPCs from human patient suffering from CTNS deficiency, i.e. ocular cystinosis patient, to express functional CTNS and administer back to the human patient.
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.
THIS ACTION IS MADE FINAL. 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 TAEYOON KIM whose telephone number is (571)272-9041. The examiner can normally be reached 9-5 EST Monday-Friday.
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/TAEYOON KIM/Primary Examiner, Art Unit 1631
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