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 .
This is in response to Applicant’s papers filed 07/20/2026.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07/20/2026 has been entered.
Claims 1-2, 9, 11, 13, 15, 19, 22, 25, 28-30, 33, 36, 41, 46, 48 and 53-59 are pending in the application. No claims are newly added, claims 1-2, 15, 19, 22, 25, 33, 36, 41, 48 and 56-58 are amended, and claims 3, 4, 6, 7, and 52 are canceled as set forth in the claim set filed 07/20/2026.
Therefore, claims 1-2, 9, 11, 13, 15, 19, 22, 25, 28-30, 33, 36, 41, 46, 48 and 53-59 are examined on the merits.
Priority
This application is a 371 of PCT/US2021/026873 filed April 12, 2021.
Applicant’s claim for the benefit of provisional applications 63/121,777 filed 12/04/2020 and 63/009,218 filed 04/13/2020 is acknowledged.
Thus, the earliest possible priority date for the instant application is April 13, 2020.
Response to arguments
Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112
The rejection of claim 15, 22, 25, 33, 36, 41, 48, 56, and 59 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second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter is withdrawn.
Applicant’s arguments and amendments filed 07/20/2026 have been considered and are persuasive. Applicant has amended to remove the recitation of “and/or”, clarifies the selecting agent utilized and corrects antecedent basis.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 9, 11, 13, 15, 19, 22, 25, 28, 30, 33, 46, and 52-55 under 35 U.S.C. 102(a)(1) as being anticipated by Mendlein (WO2018195338A1) is withdrawn.
Applicant’s arguments and amendments filed 07/20/2026 have been considered and are persuasive. In particular, in light of the narrowing the species of cytokines and inhibitors as well as steroids in the independent claim to be required in the in vivo gene therapy method Examiner has reconsidered the basis of the rejection as necessitated by the filing of the RCE.
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
Claim 1, 9, 11, 13, 15, 19, 22, 25, 28, 30, 33, 46, 48, and 53-55 remain rejected under 35 U.S.C. 103 as being unpatentable over Mendlein (WO2018195338A1; IDS Reference filed 07/11/2024) in view of Neelapu (Hematological Oncology. 2019;37(S1):48–52 ).
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 07/20/2026.
Regarding claims 1, Mendlein teaches utilizing one or more immunomodulatory agents such as cytokine and/or cytokine receptor inhibitors in addition to a viral therapeutic vector delivering a therapeutic polypeptide product (p. 1, Brief Summary; p. 2, 2nd to last paragraph; p. 18, 2nd to last paragraph). The one or more cytokine and/or cytokine receptor inhibitors include anakinra and tocilizumab (p. 3-4, bridging paragraph). Additionally, dexamethasone is utilized with the anakinra and tocilizumab (p. 1, Brief Summary; p. 2, 2nd to last paragraph; p. 3, 1st paragraph). Moreover, the vector utilized can be adenoviral vectors, herpes virus vectors, vaccinia virus vectors, adeno- associated virus (AAV) vectors, and retroviral vectors (p. 20, 2nd paragraph).
However, anakinra, tocilizumab and dexamethasone as a combination of components for in vivo gene therapy are not explicitly taught in Mendlein.
Neelapu teaches utilizing tocilizumab and dexamethasone in combination to manage cytokine release syndrome which is a toxicity that occurs during the treatment of cancers with CAR T cell products (Table 2-3, Abstract, p. 51, 2nd column). Moreover, Neelapu teaches that blocking IL-1 with anakinra abrogated toxicities (p.49, 1st column).
It would have been obvious to specifically choose the combination of tocilizumab and dexamethasone and anakinra in the method of Mendlein with a reasonable expectation of success. An artisan would be motivated to do so as combinations of these compounds as well as all of the compounds being utilized for treating toxicity in therapies are known in the art as taught by Neelapu.
Regarding claim 9, as discussed above, Mendlein and Neelapu make obvious the method of claim 1. Moreover, Mendlein teaches that the one or more immunomodulatory agents include calcineurin inhibitor such as tacrolimus (p. 1, Brief Summary; p. 2, 2nd to last paragraph; p. 3, 2nd paragraph)
Regarding claim 11, as discussed above, Mendlein and Neelapu make obvious the method of claim 1. Moreover, Mendlein teaches that the one or more immunomodulatory agents include TNF-alpha inhibitors such as etanercept (p. 1, Brief Summary; p. 2, 2nd to last paragraph; p. 3-4, bridging paragraph).
Regarding claim 13, as discussed above, Mendlein and Neelapu make obvious the method of claim 1. Moreover, Mendlein teaches that the one or more immunomodulatory agents include kinase inhibitors (JAK signal inhibitors) such as baricitinib, tofacitinib, ruxolitnib, and filgotinib (p. 1, Brief Summary; p. 2, 2nd to last paragraph; p. 4, 1st paragraph).
Regarding claim 15, 19, 22, and 25, as discussed above, Mendlein and Neelapu make obvious the method of claim 1 comprising utilizing the combination of anakinra, dexamethasone and tocilizumab and claim 9 which comprises a calcineurin inhibitor. Moreover, Mendlein teaches these immunomodulatory agents with the vector are disclosed as active ingredients/agents and Mendlein teaches an effective daily dose of the active agents can be administered in a single dose or multiple in either daily, weekly or monthly intervals (p. 110, 2nd to last paragraph; p. 114, 2nd to last paragraph). Therefore, this reads on anakinra, dexamethasone, and tacrolimus administered on the same day together with the vector.
Regarding claim 28, as discussed above, Mendlein and Neelapu make obvious the method of claim 1. As Mendlein and Neelapu teach each and every method step and limitation of the claims on which claim 28 depends, the same method steps yield the same results with a reasonable expectation of success.
Regarding claim 30, as discussed above, Mendlein and Neelapu make obvious the method of claim 1. Moreover, Mendlein teaches that the vectors can transfer or encode a selectable marker so that transduced cells can be identified and generated (p. 20, 2nd paragraph).
Regarding claim 33, as discussed above, Mendlein and Neelapu make obvious the method of claim 1. Moreover, Mendlein teaches that the composition comprising the vector and immunomodulatory agents is formulated to be suitable for intravenous and subcutaneous injection (p. 109, 3rd paragraph, Example 1).
Regarding claim 46, as discussed above, Mendlein and Neelapu make obvious the method of claim 1. Moreover, Mendlein teaches that the term ‘subject’ in their invention is a mammalian subject such as a human (p. 24, line 9).
Regarding claim 48, as discussed above, Mendlein and Neelapu make obvious the method of claim 1. The combination of references does not teach explicitly that the dosing regimen of immune suppression agents is increased based on immunotoxicity levels. However, Mendlein teaches “a physician having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician could start doses of the HRS polypeptides/expressible polynucleotides and/or immunomodulatory agents employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.” Therefore, it would be obvious to one of ordinary skill in the art to optimize the parameters and base the immunomodulatory agents and viral vectors on the level of therapeutic effect an artisan would want to achieve and as taught by increase the pharmaceutical composition levels. As disclosed in the instant specification, immunotoxicity can be an inflammatory response or cytokine response, therefore, when such a parameter is measured, optimizing the levels of a cytokine inhibitor would be obvious to one of ordinary skill in the art.
Regarding claim 53-55, as discussed above, Mendlein and Neelapu make obvious the method of claims 1, 9, 11 and 13. Moreover, Mendlein teaches that the one or more immunomodulatory agents include calcineurin inhibitor such as tacrolimus, TNF-alpha inhibitors such as etanercept, kinase inhibitors (JAK signal inhibitors) such as baricitinib, tofacitinib, ruxolitnib, and filgotinib (p. 1, Brief Summary; p. 2, 2nd to last paragraph; p. 3-4).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claims 2, 29, 36, and 41 remain rejected under 35 U.S.C. 103 as being unpatentable over Mendlein (supra) and Neelapu (supra) as applied to claim 1 above, and further in view of Richter (Hematol Oncol Clin N Am 31 (2017) 771–785, of record).
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 07/20/2026.
As discussed above and incorporated herein in its entirety, Mendlein and Neelapu make obvious a method of in vivo gene therapy in a mammalian subject comprising administering anakinra, dexamethasone, and tocilizumab in addition to a viral gene therapy vector.
Regarding claims 2, 29, and 41, these references do not explicitly teach the transduction of stem cells in particular, the mobilization of stem cells, and delivery of payload into the genome of the stem cell (claim 41) or a stem cell mobilization regimen (claim 29).
Richter teaches administering in vivo therapy through the combination of intravenous injection after the mobilization of HSCs through subcutaneous injections of GSCF/AMD3100 (Figure 1; p. 2, last paragraph; p. 8, 2nd paragraph). In Richter’s studies, the in vivo transduction utilizing this method with HDAd5/35 vectors showed that the gene was integrated into the stem cell genome (p. 8, 2nd paragraph). HSC gene therapy’s goal is the lifelong correction of an underlying genetic disease and HSC in vivo gene therapy approaches aim to simplify the gene therapy process by eliminating the need for ex vivo handling of patient HSCs (Synopsis; p. 7, last paragraph).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to administer the vector of Mendlein with all of the immunomodulatory agents of Neelapu to a subject receiving in vivo therapy and transduce the subject’s HSCs when combined with a mobilizing agent such as G-CSF with a reasonable expectation of success. An artisan would be motivated to utilize Mendlein’s vector and immunomodulatory agents with a mobilization regime as Richter teaches HSC gene therapy’s goal is the lifelong correction of an underlying genetic disease and HSC in vivo gene therapy approaches aim to simplify the gene therapy process by eliminating the need for ex vivo handling of patient HSCs (Synopsis; p. 7, last paragraph). Combining a viral vector with a mobilization regime is an in vivo gene therapy method which is known in the art as taught by Richter (Figure 1). Therefore, the payload would be delivered to the stem cells with a reasonable expectation of success.
Regarding claim 36, as discussed above, Mendlein and Neelapu make obvious the method of claim 1. Moreover, Mendlein does not teach where the adenoviral vector is derived from or is an Ad5/35 or Ad35 adenoviral vector.
However, Ritcher teaches in vivo transduction with HDAd5/35 vectors which showed that the gene was integrated into the stem cell genome (p. 8, 2nd paragraph). Therefore, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date to utilize an Ad5/35 vector as an artisan would know it effectively integrates into the cell genome.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claims 56-57 remain rejected under 35 U.S.C. 103 as being unpatentable over Mendlein (supra) and Neelapu (supra) as applied to claims 1, 15 and 19 above, and further in view of Keidel (Rheumatology 2014;53:573574).
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 07/20/2026.
As discussed above and incorporated herein in its entirety, Mendlein and Neelapu make obvious a method of in vivo gene therapy in a mammalian subject comprising administering anakinra, dexamethasone, and tocilizumab in addition to a viral gene therapy vector.
However, these references do not teach the dosage of the anakinra or the tocilizumab.
Keidel teaches utilizing anakinra at a dose of 100 mg/day and tocilizumab at a dose of 8mg/kg/month in a teen subject with an inflammatory disorder (p. 573, 2nd column). If the average weight of a teen woman is 50kg, this would be approximately 13 mg/day of tocilizumab.
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to utilize anakinra at a dose of 100 mg/day and 13 mg/day of tocilizumab in the method of Mendlein with a reasonable expectation of success. An artisan would have been motivated to do so as Keidel demonstrates that the dosages are known in the art to treat inflammatory conditions.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claims 58-59 are newly rejected under 35 U.S.C. 103 as being unpatentable over Mendlein (supra) and Neelapu (supra) as applied to claims 1 and 30 above, and further in view of Ball (Blood (2004) 104 (11) : 2109)
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 07/20/2026.
As discussed above and incorporated herein in its entirety, Mendlein and Neelapu make obvious a method of in vivo gene therapy in a mammalian subject comprising administering anakinra, dexamethasone, and tocilizumab in addition to a viral gene therapy vector.
However, these references do not teach administering to the subject a selecting agent such as O6BG/BCNU or that the selectable marker is MGMTP140K.
Ball teaches bone marrow cells from mice transduced with an MGMT/IRES/eGFP encoding retroviral vector and transplanted into recipient mice. Starting 4 weeks post-transplant, the mice were treated monthly with two reduced dosages of O6 BG and BCNU (p. 2) Overall, “successful selection of gene modified hematopoietic stem cells against the majority of non-modified cells may increase the efficiency and safety of clinical gene therapy. Especially if a reduction of the intensity of the myelotoxic pre-transplant conditioning treatment is sought, selection of the initially low percentage of retrovirally gene modified stem cells is required. In addition to the decreased drug related toxicity, such a procedure reduces the risk of genotoxicity caused by insertional mutagenesis simply by diminishing the likelihood of transplanting stem cells that carry unwanted insertion sides compared to strategies that attempt to increase efficiency by increasing vector dose and/or the number of engrafted gene-modified cells. To date, the mutant O6-methylguanine-DNA methyltransferase (MGMT) enzyme that confers resistance to nitrosoureas such as BCNU is the drug-resistance gene that allows most efficient selection at the stem cell level.” (p. 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer to the subject a selecting agent such as O6BG/BCNU and encode a selectable marker such as MGMTP140K with a reasonable expectation of success. An artisan would have been motivated to utilize both the agent and the marker as successful selection of gene modified hematopoietic stem cells against the majority of non-modified cells may increase the efficiency and safety of clinical gene therapy as well as such a procedure which reduces the risk of genotoxicity caused by insertional mutagenesis.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
In response to Applicant’s arguments and amendments filed 07/20/2026 regarding the 103 rejections,
Applicant’s arguments and amendments have been considered, however they are not persuasive.
Applicant’s arguments regarding the deficiency of Mendlein for specific combinations of compounds have been addressed above and Neelapu has been provided to demonstrate the combinations are known in the art and that an artisan would have been motivated to utilize them together.
Applicant further argues that there is no motivation to combine Mendlein with Ritcher and that when looked at as a whole, there is only a distinct strategy from Richter for HSC gene therapy and that the Office relied on the stated purpose of the inventions which are distinct. Moreover, Richter does not teach the HRS polypeptide of Mendlein.
The Examiner first, states that the intended use or purpose of Richter was relied upon to show the advantages and motivation for mobilization of HSCs and utilizing the specific vector serotype in HSC therapy, this does not attempt to bodily incorporate all of Richter’s method into Mendlein and Ritcher is not required to disclose the HRS polypeptide to provide teaching, suggestion or motivation for mobilization in HSCs. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Applicant argues that Keidel shows that anakinra and tocilizumab was utilized in alternative and not together and therefore, one would be motivated to exclude anakinra.
Examiner states that Keidel provides known dosages utilized in the art for the compounds and teachings and motivation has already been established in Neelapu and Mendlein.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA CONNORS whose telephone number is (571)272-7010. The examiner can normally be reached Monday - Friday (9AM-5PM).
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, MARIA LEAVITT can be reached at (571) 272-1085. 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.
/ALEXANDRA F CONNORS/ Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
Prosecution Insights