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 .
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4, 9-14, and 16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bhandoola et al. (US 2014/0037599 A1)
Regarding Claims 1 and 15: Bhandoola discloses methods for creating a genetically modified T cell progenitor cell with an embodiment of the invention being transfected via a retroviral vector (0006). Bhandoola further discloses that the media used in the claimed invention comprises Fungizone, which is a commercially available brand of Amphotericin B. This reads on the claimed method of transducing a target cell with the target cell being co-stimulated with a transduction enhancing compound during contact of the target cell with a retroviral vector.
Regarding Claims 2 and 17: Bhandoola discloses use of Fungizone in the media composition of their claimed invention, in particular at a concentration of 25uG. (0045) As disclosed above, Fungizone is a commercially available brand of Amphotericin B. Use of Fungizone at a concentration of 25uG reads on the claimed method of “about 0.05 to about 10uM”, as when converted to uM, 25uG is equivalent to 0.03uM, which reads on the claimed range of about 0.05-10uM. Therefore, use of Fungizone at 25uG reads on both claims 2 and 17.
Regarding Claims 3 and 4: Bhandoola discloses an embodiment of the invention detailing use of protamine sulfate (0098) during transduction, which reads on the method of claim 4. This combined with use of Fungizone in the culture media reads on the method of claim 3, which details use of Amphotericin B in conjunction with one or more additional transduction enhancing compounds.
Regarding Claim 9: Bhandoola discloses an embodiment of the invention where the incubation of the target cell with the transfection agent for a range of about 3 hours to about 14 days. This reads on the claimed method of “particularly about 8-48 hours”.
Regarding Claim 11: Bhandoola discloses a preferred embodiment of the invention which uses human T cell progenitor cells (TCPCs) as the target cell. (0035) As humans are a type of mammal, this satisfies the requirement of claim 11.
Regarding Claim 12: Bhandoola discloses an embodiment of the invention where the target TCPCs express TCF-1, TCF-3, TCF-4, or TCF-10 which leads to T cell differentiation. (0035) This reads on the claimed method of use of T cells as the target cell.
Regarding Claim 13: Bhandoola discloses an embodiment of the invention in which T cell progenitor cells are used as a target cell. (0035) TCSCs are a type of haematopoietic progenitor cell, therefore reading on the claimed method of use of a haematopoietic progenitor cell.
Regarding Claim 14: Bhandoola discloses an embodiment of the invention in which the target T cell exhibits at least one marker derived from the group consisting of CD2, CD3, CD25, CD4, and CD8.
Regarding Claim 16: Bhandoola discloses an embodiment of the invention which uses a transgene linked to a suitable promoter (0084) that may be used in the context of gene therapy and may encode a second transgene (0083) and may include nucleic acids which cause the transfected cell to transcribe proteins in vitro or in vivo. (0086) This reads on use of a transgene under control of a promoter.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Bhandoola et al. (US 2014/0037599 A1) in view of Yang et al. (Protamine Sulfate Enhances the Transduction Efficiency of Recombinant Adeno-Associated Virus-Mediated Gene Delivery, 2001)
The teachings of Bhandoola et al. are disclosed above. Bhandoola fails to teach use of a protamine salt at a ratio of about 0.05uG/mL to 25mg/mL.
Regarding Claim 5: Yang et al. teaches that transduction of HepG2 cells with rAAV at a MOI of 500 in the absence of protamine sulfate results in a transduction efficiency of approximately 37%. Addition of 5uG/mL protamine sulfate increased the transduction efficiency to 54%. (Pg 925, Fig 3A) This reads on the method of Claim 5, which states that the protamine salt is present in the incubation step at a concentration of about 0.05uG/mL to about 25mg/mL.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the ratio of protamine sulfate as taught by Yang with the transduction protocol taught by Bhandoola to use specifically 5uG/mL of protamine sulfate to increase the efficiency of the transduction protocol. One would have been motivated to do so and had a reasonable expectation of success due to the teachings of Yang, who details that the addition of 5uG/mL protamine sulfate significantly increased the transduction efficiency of HepG2 cells with rAAV.
Claims 6, 20, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Bhandoola et al. (US 2014/0037599 A1) in view of Chen et al. (Retinoic acid and dimethyl sulfoxide promote efficient delivery of transgenes to mouse skin by topically transdermal penetration, 2010)
The teachings of Bhandoola et al. are disclosed above. Bhandoola fails to teach a specific range of DMSO used to aid in the transfection of T cell progenitor cells.
Regarding Claim 6: Chen et al. teaches that DMSO aids in transdermal efficacy of a target gene to mouse skin (dermal cells) (pg 385, Abstract) and tests DMSO in concentrations of 30%, 10%, 5%, and 0%. (Pg 386, DMSO and plasmid DNA mixture preparation) This reads on the method of claim 6 of use of a transduction enhancing compound (DMSO).
Regarding Claim 20: Following the discussion of claims 6 and 7 above, the teachings of Chen further read on claim 20 due to Chen teaching use of DMSO at concentrations of 30%, 10%, 5%, and 0%. (Pg 386, DMSO and plasmid DNA mixture preparation) This satisfies the requirement of claim 20 of use of DMSO at a concentration between 0.1-10% as the additional transduction enhancing compound.
Regarding Claim 23: Chen teaches a method of therapeutic transgene delivery for dermal use to aid the dermis (pg 385, Abstract), reading on the claimed method of the transgene encoding a therapeutic protein.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of TCSC transduction as taught by Bhandoola with use of DMSO as a transduction enhancing compound as taught by Chen to create a method of transduction with enhanced cellular penetration efficiency. One would have had a reasonable expectation of success and motivation to do so based on the teachings of Chen, who details that use of DMSO aids in gene to skin penetration and transfer.
Claims 15 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Bhandoola et al. (US 2014/0037599 A1) in view of Zufferey et al. (Self-Inactivating Lentivirus Vector for Safe and Efficient In Vivo Gene Delivery, 1998
The teachings of Bhandoola et al. are disclosed above. Bhandoola fails to teach use of a self-inactivating lentiviral vector.
Regarding Claim 15: Zufferey et al. teaches a method of improving a lentiviral vector by removing the transcriptional elements of HIV from the vector (pg 9873, left column, first full paragraph), specifically by deletion of a 400-nucleotide long component in the U3 region of the HIV-1 3’ LTR. (Pg 9874, Results) Removal of the LTR sequence prevents transcriptional interference and suppression in vivo and allows for the construction of more tissue-specific vectors. (Pg 9873, Abstract) Importantly, Zufferey found that the deletion of the region did not impact vector titers. (Pg 9874, Results) This reads on the claimed method of use of a lentiviral vector.
Regarding Claim 22: Zufferey teaches a method for the transduction of a self-inactivating lentiviral vector. (Pg 9873, Abstract) This reads on claim 22 regarding use of a self-inactivating lentiviral vector.
It would have been obvious for a person of ordinary skill in the art to combine the transcription method as taught by Bhandoola with the addition of a self-limiting lentiviral vector as taught by Zufferey to create a self-limiting construct for transfection of TCPCs. One would have been motivated to do so based on the teaching of Zufferey, which states that self-limiting lentiviral vectors help prevent transcriptional interference and suppression.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Bhandoola et al. (US 2014/0037599 A1) in view of Hikada et al. (Amphotericin B Enhances Efficiency of DNA-Mediated Gene Transfer in Mammalian Cells, 1985)
Regarding Claim 21: Bhandoola teaches use of a retroviral vector for transfection. (0006). Bhandoola further teaches use of Fungizone, but fails to specify the co-incubation time of between about 10-24 hours.
Hikada teaches that use of amphotericin B as a transfection enhancement agent (pg 109, Abstract) and further teaches co-incubation of amphotericin B with CaPO4-precipitated DNA for 20h. (Pg 110, Materials and Methods) This reads on claim 21 regarding co-incubation of amphotericin B for about 10-24 hours.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teaching of Hidaka of use of an incubation time of 20h with the teachings of Bhandoola to create an incubation timeframe with the retroviral vector and amphotericin B (Fungizone) of between about 10-24h. One would have motivation and a reasonable expectation of success at doing so based on the teachings of Hikada, who state that amphotericin B is an effective enhancer of both genotypic and phenotypic transfection. (Pg 113, Discussion)
Response to Arguments
Applicant argues that while Bhandoola discloses use of Fungizone (Amphotericin B) in the cell culture media, Bhandoola fails to specify use of Fungizone specifically for the use of aiding in transduction efficiency. However, it is inherent that by virtue of being present in the media during the time of transfection that the Fungizone would still aid in transfection efficiency, even though that purpose is not outright stated. Applicant additionally argues that the media comprising Fungizone in the cell culture medium is used for cell culture purposes only and no for transduction, however in a given example of the invention, Bhandoola explicitly states that high-titre retroviral supernatants were added into wells (0167), not that the base cell culture media (comprising Fungizone) was removed. As such, the base media containing Fungizone is present at the time of transfection.
Applicant further argues that the rejections under Bhandoola in combination with Yang (claims 5 and 8), Chen (claims 6 and 7), and Zufferey (claim 15) should be withdrawn based on the same argument of Bhandoola of not teaching intended use of Fungizone. Based on the discussion above, those arguments are found unpersuasive on the same basis.
Lastly, Applicant argues that a person of ordinary skill in the art would have no reason to combine the following teachings:
The teachings of Yang of use of use of a protamine salt in conjunction with the use of Fungizone as taught by Bhandoola
The teachings of Chen of use of DMSO as a transduction efficiency aid in conjunction with the use of Fungizone as taught by Bhandoola
The teachings of Zufferey of use of a self-inactivating lentiviral vector in conjunction with the teachings of use of Fungizone as taught by Bhandoola.
In response, Examiner notes that MPEP 2141.2.C states that "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton."KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle."Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ."Id. at 418, 82 USPQ2d at 1396.
Conclusion
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 HANNA M THUESON whose telephone number is (571) 272-3680. The examiner can normally be reached M-F 7:30-5 EST. 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.
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/HANNA MARIE THUESON/ Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638