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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 5/21/2026 has been entered.
Election/Restrictions
Applicant's election with traverse of species: human TPP1, CMV enhancer, VP1, CSF, LINCL and cerebellum in the reply filed on 8/8/2022 is acknowledged. The traversal is on the grounds that searching all of the species would not be a burden. This is not found persuasive because this is a 371 application and a search burden is not a consideration.
The requirement is still deemed proper and is therefore made FINAL.
Claims 9-10, 61 and 68 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 8/8/2021.
Claims 1, 4-8, 12, 14-15, 19, 25, 31, 33-34, 37, 41, 44-49, 51-57, 60 and 65 are under consideration in the instant Office Action.
Maintained Rejections
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, 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.
Claims 1, 4-8, 12, 14-15, 19, 25, 31, 33-34, 37, 41, 44-49, 51-57, 60 and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Davidson et al., WO2015/013148 (IDS) in view of Ciron et al., 2006 (10/27/2022 PTO-892).
Davidson teaches methods of treating a disease by delivering a therapeutic agent to a mammal comprising administering to the mammal’s ventricle or cisterna magna an rAAV particle contains a vector comprising a nucleic acid encoding a therapeutic protein inserted between a pair of AAV inverted terminal repeats (ITR) in a manner such as that cells with access to the cerebrospinal fluid (CSF) express the therapeutic agent or secretes the therapeutic agent into the CSF for distribution to the brain (see abstract, page 2, page 7, page 11, lines 24-28) as in instant claims 1 and 44. Davidson teaches that the cells that express the therapeutic agent and secretes the therapeutic agent in to CSF includes the ependymal cells (see page 3, lines 3-10) and meets the new limitation instant claims 1 and 44. This teaching meets the intended result of instant claim 1 since Davidson teaches the same patient population being administered the same treatment via the same route which would produce the same results as now claimed. MPEP 2112.02 states 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) (Claims 1 and 6, directed to a method of effecting nonaddictive analgesia (pain reduction) in animals, were found to be anticipated by the applied prior art which disclosed the same compounds for effecting analgesia but which was silent as to addiction. The court upheld the rejection and stated that the applicants had merely found a new property of the compound and such a discovery did not constitute a new use. The court went on to reverse the obviousness rejection of claims 2-5 and 7-10 which recited a process of using a new compound. The court relied on evidence showing that the nonaddictive property of the new compound was unexpected.). See also In re Tomlinson, 363 F.2d 928, 150 USPQ 623. "While the references do not show a specific recognition of that result, its discovery by appellants is tantamount only to finding a property in the old composition." 363 F.2d at 934, 150 USPQ at 628 (emphasis in original)).
Davidson teaches that the therapeutic agent includes lysosomal hydrolases that include nucleic acid of human TPP1 protein (see page 3, lines 30-33 and page 4, Figure 3 and Figure 14, page 10, lines 10-25, page 12, lines 10-11) as in instant claims 1 and 5-7. Davidson teaches that the AAV particle is an rAAV2 particle and that the rAAV capsid has at least 80% homology to the AAV2 capsid protein VP1 (see page 2, lines 16-33, spanning pages 7-8, page 10, lines 26-30) as in instant claims 4, 15, 19, 52 and 65. Davidson teaches promotors that include cytomegalovirus (CMV, see page 8, lines 15-20, page 20- lines 14-21) as in instant claims 8, 12 and 14. Davidson teaches methods of treating lysosomal storage disease (LSD) which include infantile or late infantile ceroid lipofuscinoses (LINCL, see page 3, lines 18-27) as in instant claims 1 and 51. Davidson teaches the treatment of mammals that are non-rodent mammals and include primate and human (see page 3, lines 28-30) as in instant claims 46-48. Davidson teaches treating LINCL pups with gene therapy with AAV2-CLN2 ( producing TTP1) by injecting into the brain at the ventricle or cisterna magna (see page 31) and as in instant claims 1, 25 and 52. Davidson teaches a dose that includes about 1-5ml of 1x105-1016 vg/ml (see page 23, lines 29-32) as in instant claim 41. Davidson teaches increased activity of TTP1 in the cerebellum, thalamus, hippocampus, spinal cord and other tissues and cells when treated with AAV2-CLN2 (see Figure 8) as in instant claim 60. Davidson teaches in their Figure 10 and page 5 the delay of onset of symptoms associated with LSD which include symptoms like proprioceptive ataxia, menace and resting and intention tremors as in instant claims 53-54.
With regard to claims 45, 55-57 which depend from claim 1, and wherein the treated animals exhibit functional effects of the methodology, the claims require no additional steps. 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.
Davidson teaches the method steps of claim 1, as iterated above but does not explicitly teach the claimed effects of claims 45 and 55-57. Davidson performs the same method steps as claimed and therefore, would also produce the claimed effects of claims 45 and 55-57, even if not explicitly disclosed. Davidson does no teach administering immunosuppressive agents comprising cyclosporine and mycophenolate.
Ciron teaches administering AAV particles encoding alpha-L-iduronidase (IDUA) to the brain of dogs of a Hurler Syndrome Lysosomal storage Disease model, wherein the AAV particles transduce and express the recombinant IDUA, and wherein the dogs are subjected to immunosuppressive therapy comprising administering cyclosporine and mycophenolate to the dogs at least three weeks before the AAV particles were injected in the brain (see Abstract, pages 205-206, Table 1; Fig 1) as in instant claims 1, 31, 33-34, 37, 46-47 and 51. Ciron discloses the AAV particles are administered to the tissue of the brain (page 205, page 210) as in instant claim 1. Ciron teaches using alpha-L-iduronidase (IDUA) which is a lysosomal hydrolase as in instant claim 1. Ciron shows the IDUA has hydrolysis activity (IDUA assay, page 206, FIG 1). Ciron teaches the LSD is Hurler Syndrome Lysosomal Storage Disease. Ciron discloses the AAV particles were generated according to Desmaris, 2004. Desmaris is cited solely to show that the IDUA enzyme was encoded on a nucleic acid that is flanked by a pair of AAV ITRS (see page 69 “Adenoassociated Virus Vector Construction and Production” Section) as in instant claim 1. Ciron teaches administering AAV5.5hIDUA at 1.5x1012 genomes/ml (see page 205) as in instant claim 41.Ciron teaches administering cyclosporine and mycophenolate mofetil to the dogs at least three weeks before the AAV particles were injected into mammals such as dogs (abstract, Table 1) as in instant claims 1, 31, 33-34, 37, 46 and 52. Ciron teaches administering the gene therapy treatment to children with Hurler’s syndrome (see page 213) as in instant claims 47-49.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Davidson and Ciron. The person of ordinary skill in the art would have been motivated to make and use the invention as claimed because Davidson teaches using gene therapy to treat LSD diseases by administering the deficient enzyme the same way as Ciron does. One of ordinary skill in the art would be motivated to administer the treatment for LINC as taught by Davidson with the immunosuppressive agents comprising cyclosporine and mycophenolate as taught by Ciron to prevent severe unwanted effects (see Ciron, page 211, 1st column) since both Davidson and Ciron are treating lysosomal storage diseases by administering polypeptides with lysosomal hydrolase activity via gene therapy. Further, one of ordinary skill in the art would apply the treatment taught by Davidson to a child as taught by Ciron since these lysosomal storage diseases are inherent and affect a child early on in development and one ordinary skill in the art would want to reduce the amount of harm as soon as possible in the patient population. The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 4-7, 25, 31, 33, 37, 44-48, 51-57, 60 and 65 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,391,184. Although the claims at issue are not identical, they are not patentably distinct from each other because ‘184 discloses a method of delivering a therapeutic agent to the central nervous system of a mammal, comprising administering to the mammal's brain ventricles an rAAV particle comprising an AAV capsid protein and a vector comprising a nucleic acid encoding a therapeutic agent inserted between a pair of AAV inverted terminal repeats in a manner effective to infect a cell that contacts the cerebrospinal fluid (CSF) of the mammal such that the cell expresses the therapeutic agent in the mammal. ‘184 further specifies the administration of an immunosuppression agent, alternatively the route of administration can be by brain ventricle, subarachnoid space, or intrathecal space, the therapeutic agent is TPP1 and the mammal is a primate. ‘184 specifies that the method also administers an immunosuppression agent including mycophenolate, the route of administration can alternatively also be by brain ventricle, subarachnoid space or intrathecal space, the disease is LINCL, the therapeutic agent is TPP1 or CLN2, and the mammal is a primate and therefore, anticipates the instant claims.
Claims 1, 4-7, 31, 33-34, 37, 41, 44-49, 51-57, 65 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 11-24 of U.S. Patent No. 9,849,195 in view of Ciron et al., 2006 (10/27/2022 PTO-892).
Although the claims at issue are not identical, they are not patentably distinct from each other because ‘195 discloses a method of treating a CNS disease with a therapeutic agent delivered to the central nervous system of a mammal, comprising administering to the mammal's CSF via intraventricular administration an rAAV particle comprising an AAV capsid protein and a vector comprising a nucleic acid encoding a therapeutic agent, TTP1, inserted between a pair of AAV inverted terminal repeats in a manner effective to infect a cell that contacts the cerebrospinal fluid (CSF) of the mammal such that the cell expresses the therapeutic agent in the mammal including primates and humans. ‘195 does not teach.
Ciron teaches administering AAV particles encoding alpha-L-iduronidase (IDUA) to the brain of dogs of a Hurler Syndrome Lysosomal storage Disease model, wherein the AAV particles transduce and express the recombinant IDUA, and wherein the dogs are subjected to immunosuppressive therapy comprising administering cyclosporine and mycophenolate to the dogs at least three weeks before the AAV particles were injected in the brain (see Abstract, pages 205-206, Table 1; Fig 1) as in instant claims 1, 31, 33-34, 37, 46-47 and 51. Ciron discloses the AAV particles are administered to the tissue of the brain (page 205, page 210) as in instant claim 1. Ciron teaches using alpha-L-iduronidase (IDUA) which is a lysosomal hydrolase as in instant claim 1. Ciron shows the IDUA has hydrolysis activity (IDUA assay, page 206, FIG 1). Ciron teaches the LSD is Hurler Syndrome Lysosomal Storage Disease. Ciron teaches administering AAV5.5hIDUA at 1.5x1012 genomes/ml (see page 205) as in instant claim 41.Ciron teaches administering cyclosporine and mycophenolate mofetil to the dogs at least three weeks before the AAV particles were injected into mammals such as dogs (abstract, Table 1) as in instant claims 1, 31, 33-34, 37, 46 and 52. Ciron teaches administering the gene therapy treatment to children with Hurler’s syndrome (see page 213) as in instant claims 47-49.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of ‘195 and Ciron. The person of ordinary skill in the art would have been motivated to make and use the invention as claimed because ‘195 teaches using gene therapy to treat LSD diseases by administering the deficient enzyme the same way as Ciron does. One of ordinary skill in the art would be motivated to administer the treatment for LINC as taught by ‘195 with the immunosuppressive agents comprising cyclosporine and mycophenolate as taught by Ciron to prevent severe unwanted effects (see Ciron, page 211, 1st column) since both ‘195 and Ciron are treating lysosomal storage diseases by administering polypeptides with lysosomal hydrolase activity via gene therapy. Further, one of ordinary skill in the art would apply the treatment taught by ‘195 to a child as taught by Ciron since these lysosomal storage diseases are inherent and affect a child early on in development and one ordinary skill in the art would want to reduce the amount of harm as soon as possible in the patient population. The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Response to Arguments
Applicant's arguments filed 5/21/2026 have been fully considered but they are not persuasive. Applicant argues that neither Davison nor Ciron teach the specific site of administration of TPP1 to caudal ventricle. This is not found persuasive because Davidson teaches administration of the therapeutic agent includes lysosomal hydrolases that include nucleic acid of human TPP1 protein (see page 3, lines 30-33 and page 4, Figure 3 and Figure 14, page 10, lines 10-25, page 12, lines 10-11). Davidson also teaches delivering a therapeutic agent to a mammal comprising administering to the mammal’s ventricle and rAAV particle contains a vector comprising a nucleic acid encoding a therapeutic protein inserted between a pair of AAV inverted terminal repeats (ITR) in a manner such as that cells with access to the cerebrospinal fluid (CSF) express the therapeutic agent or secretes the therapeutic agent into the CSF for distribution to the brain (see abstract, page 2, page 7, page 11, lines 24-28). The mammal ventricle encompasses the required caudal lateral ventricle and therefore, meets this limitation and anticipates the instant claims. Therefore, the Davidson reference teach the instantly claimed treatment and provides clear guidance of where to administer the instantly claimed treatment.
Applicant argues that the administration site of the required caudal lateral ventricle of the method is a critical part of the innovation of the formulated AAV compositions. Applicant argues that Examples 3-7 of the instant specification demonstrate the unexpected results of the claimed methods and that the site of administration, specifically rostral or caudal of the lateral ventricles, is part of the criticality. This is not found persuasive.
As previously discussed, the CNS ventricular system is made of 4 ventricles. The 2 lateral ventricles, the third ventricle and fourth ventricle which are all interconnected and have CSF flowing though out these ventricles. As evidenced by the figure below, the lateral ventricles are the largest ventricles and the rostral (towards the face) and caudal (back of head) areas of the ventricles encompass all of the possible areas of the lateral ventricles. Therefore, the claim limitations are not as specific as applicant seems to infer. Further, since all of the ventricles are interconnected, there is no evidence of when administering the treatment to the ventricles, as claimed, that the placement will be limited to only a specific area of the ventricles. The instant specification does not even support this statement since the paragraphs 169-170 of the instant specification discloses that the viral vector is transferred to other ventricles like the fourth ventricle via the CSF after administration of the viral vectors to the lateral ventricle.
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(https://rotel.pressbooks.pub/biologicalpsychology/chapter/non-neuronal-structures-in-the-central-nervous-system/; 6/20/204 PTO-892)
The Example 3-7 of the instant specification fail to support the applicant’s argument for the critically of the administration sight of specific caudal or rostral lateral ventricular administration. The instant specification points out that their administration of the viral vector in mice is 10ml in volume which takes 2/3s of the total volume of 15ml in mouse ventricles and that basically they are flooding the ventricles with the viral vector, see paragraph 155 of the instant specification. Therefore, there is no evidence provided in the instant specification for critically shown for the limitation of instant claim 1 as argued by applicant. The main reason to target the lateral ventricles as the site for treatment administration is that they are the largest structure of the ventricles and is the best route to get it to spread through the CSF that runs through these structures.
It would have been prima facie obvious to one of ordinary skill in the art to choose different site of administration within the ventricles; such would amount to choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; which is proper to support a finding of obviousness under 35 U.S.C. 103(a). See the Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (See also MPEP §2143(E). The prior art of record teaches all of the required limitations for the construct to be administered and even the site of administration, the ventricles. The fact that applicant observed a difference within the disclosed site does not make it unexpected or significant in producing the desired effect of treating a lysosomal storage disease.
The evidence provided by applicant in the Appendix A is still not sufficient to overcome the 103 obvious rejection over unexpected results. The prior art, Davidson, also teaches the transfection of these cells with the claimed vector.
Further, the actual data presented in this appendix is not within the same scope as the instant claims since it appears the data was generated in two African green monkeys at two different delivery sited but is not the same AAV but rather a AAV-Ep+mRuby3. This is not the vector that is part of the instant claims. It is unclear how the claimed AAV with TPP1 is similar or even the same as the a AAV-Ep+mRuby3 used in these examples. Applicant still has not provided evidence of the unexpected expression of TTP1 expression but rather provided evidence that ependymal cell are capable of being transduced. The only thing applicant has shown is that proximity of the a AAV-Ep+mRuby3 vector can transfect the ependymal cells in its proximity to the site injection, due to low availability of the vector which cannot disperse further into the other site and locations in the ventricles. There is no support for the unexpected increase in TTP1 expression at the caudal site of the lateral ventricle. The instant claims are towards a method treating a lysosomal storage disease and the method leads to TPP1 expression level in the CSF. These limitations are all met by the prior art and there is reasonable expectation of producing the same effect as the instant claims over the teaching provided in the prior art. Applicant has not shown that the specific location of transfection on all other ventricles is critical to produce the required effective treatment of the LSD. This argument and evidence is towards the spread of transfection. Therefore, there is no reasoning why it matters or even why is it critical to transfect all of the ventricles with the vector expressing TPP1 since all the ventricles are directly in contact with CSF. Once a majority of ependymal cells are transfected with administered vector, the cells would produce the required TPP1 and release it to the CSF and therefore, producing the required treatment.
Therefore, the arguments and declaration are not found persuasive and the rejections are maintained.
Applicant's arguments against the double patenting rejections of the instant claims over of the applications and patents are the same augments in regards to criticality of route of administration. See the response, as set forth above. The double patenting rejections are maintained for the same rational, as discussed above.
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
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/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675
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