DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims 1-24 have been canceled. Claims 25-51 remain pending.
Election/Restrictions
Applicant's election with traverse of Group II, claims 39-51, in the reply filed on 9-13-26 is acknowledged. Upon reconsideration, Groups I and II have been combined.
Claims 25-51 are under consideration.
Claim objections
Claim 25 can be written more clearly as: ---A genetically modified isolated mammalian T-cell whose genome comprises a replacement of a nucleic acid sequence encoding an endogenous immunological checkpoint gene with a nucleic acid sequence encoding a chimeric antigen receptor (CAR) such that expression of the immunological checkpoint gene is inactivated and the T-cell functionally expresses the CAR---.
Claim 39 can be written more clearly as: ---A method of making a genetically modified mammalian T-cell that expresses a chimeric antigen receptor (CAR), the method comprising: introducing a nuclease and a nucleic acid sequence encoding a CAR into an isolated mammalian T-cell such that a coding sequence of an endogenous programmed death receptor 1 (PD1) or [CTLA4] gene is replaced with the nucleic acid sequence encoding a CAR---.
These suggestions are not to be construed as allowable subject matter because of the immense breadth claimed and because of the rejections below.
Claim interpretation
PDCD1 (“programmed cell death 1”) is also known as PD1.
Claim Rejections - 35 USC § 112
Enablement
Claims 25-51 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for making an isolated human T-cell whose genome comprises: i) an inactivated PD1 gene made using a pair of TALENs (pg 59, Example 2) or ZFNs (pg 62, Example 4) or an inactivated CTLA4 gene made using a pair of TALENs (pg 59, Example 2); and ii) whose genome comprises an exogenous nucleic acid sequence encoding a chimeric antigen receptor (CAR), wherein the T-cell functionally expresses the CAR and does not express PD1 or CTLA4 does not reasonably provide enablement for performing the method in any species of T-cell other than human, performing the method in vivo, using any “nuclease”, e.g. Cas9 or ZFNs, introducing the CAR sequence into any immunological checkpoint gene without inactivating a PD1 or CTLA4 gene using CRISPR technology as broadly encompassed by claim 39, using ZFNs to inactivate a CTLA4 gene. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The specification does not enable using any nuclease to insert a CAR sequence into any safe harbor or immuno-checkpoint gene of any T-cell as broadly encompassed by claim 39.
Claim 25 is drawn to a genetically modified T-cell that expresses a chimeric antigen receptor (CAR), wherein an exogenous sequence encoding a CAR is integrated into the genome of the T-cell using one or more nucleases, and wherein expression of at least one endogenous immunological checkpoint gene is repressed in the T-cell.
Claim 39 is drawn to a method of making a genetically modified T-cell that expresses a chimeric antigen receptor (CAR), wherein an exogenous sequence encoding a CAR is integrated into the genome of the T-cell using one or more nucleases, and wherein expression of at least one endogenous immunological checkpoint gene is repressed in the T-cell comprising introducing an exogenous sequence encoding a CAR into the genome of the T-cell using a nuclease such that the exogenous sequence encoding the CAR is integrated into the genome of the cell at the location of a safe harbor gene or an endogenous immunological checkpoint gene.
Claims 25 and 39 encompass integrating the exogenous nucleic acid sequence encoding a CAR into any safe harbor or immune-checkpoint gene including PD1 or CTLA4 using ZFNs.
The claims encompass using any single ZFN, meganuclease, TALEN, or Cas9 or any pair of ZFNs or TALENs.
The cells may be fish, amphibian, reptile, bird, or mammalian.
The cells may be in vivo or in vitro.
The safe harbor gene may be Rosa26, AAVS1, CCR5, et al.
The immuno-checkpoint gene “include members of the extended CD28 family of receptors and their ligands as well as genes involved in co-inhibitory pathways (e.g., CTLA-4 and PD-1)” (pg 16, end of para 50) (PD1 is discussed on pg 2, para 5; CTLA4 is discussed on pg 3, para 6).
The claims do not require that the CAR is functionally expressed in the T-cell.
The claims do not require the safe harbor or immuno-checkpoint gene is inactivated.
The specification does not enable using any nuclease as broadly encompassed by claims 25 and 39 other than a pair of TALENs that inactivate an endogenous human PD1 gene (pg 59, Example 2), a pair of ZFNs that inactivate an endogenous human PD1 gene (pg 62, Example 4), or a pair of TALENs that inactivate an endogenous human CTLA4 gene (pg 59, Example 2).
Modifying a gene in cells using a ZFN was unpredictable as evidenced by Porteus (Nature Biotech., 2005, Vol. 23, No. 8, pg 967- 973), who taught ZFNs have been primarily applied to transformed mammalian cell lines that are relatively resistant to apoptotic stimuli, but not primary cells that are more sensitive to DNA damage (see page 971, 2nd col., 3re paragraph). One of the challenge of applying this method to primary cells is the delivery method, wherein the method of transformation that is suitable for cultured cell line is applicable to primary cell is unpredictable, thus remains as the area of future study (see page 972, 1st col., 3rd paragraph). Porteus taught other challenges remain in the field of developing ZFNs to stimulate gene targeting by homologous recombination. Such challenges include: 1) applicability of the ZFN approach needs to be broadened; 2) the method of delivering ZFNs and repair substrate to cells requires optimization; and 3) understanding the process of homologous recombination itself. Porteus points out that the optimization of ZFN design must address two key questions of specificity and cytotoxicity (see page971, 3re-5th paragraph).
Ramirez (Unexpected failure rates for modular assembly of engineered zinc fingers. Nature Methods, 2008, 5(5): 374-375) call into question the predictability of modularly designing zinc finger proteins to bind to nucleic acid triplets in the zinc finger DNA binding sites, and of successfully making nuclease fusion proteins of these zinc finger proteins to successfully cleave the zinc finger DNA binding sites.
Reik (US Patent Application 2008/0188000) taught the nature of the mutation made using a nuclease was unpredictable. Example 3 (pg 14-15; paragraph 159) discusses the nature of the mutation made using zinc finger binding domains 8667 and 8668. Various mutations were obtained including a 2-nucleotide deletion, an 11-nucleotide deletion, a "mixture of sequences: one of which was a duplication of four nucleotides, the other of which was a 19- nucleotide deletion" (paragraph 120). Example 3 does not teach any of the mutations caused the GR gene to be inactivated or how to use the cells having the various modifications to the GR gene.
Geurts (Science, July 24, 2009, Vol. 325, pg 433) taught a rat whose genome had a homozygous disruption in an endogenous gene made using a zinc-finger nuclease (ZFN). The ZFN had “tandem repeats” that interact with endogenous DNA in a specific manner and dimerized to cut DNA encoding GFP, IgM and Rab38 genes.
Christian (Genetics, available online 7-26-08, Vol. 186, pg 757-761) taught the barrier to the widespread adoption of ZFNs has been the challenge in engineering DNA binding specificities. Generating “the necessary reagents to modify new DNA targets” is “to some degree empirical” (based on observation/experience rather than theory or pure logic; pg 757, col. 1, 1st paragraph). “To realize the potential of TALENs for genome modification, it will be necessary to engineer them to recognize novel chromosomal DNA sequences. Randomly assembled repeat domains have been shown to bind DNA targets predicted by the cipher… …; however, custom TALEs designed to recognize new target sequences have not been reported. This is an important distinction, because the former experiments validate the cipher, whereas the latter would demonstrate that DNA binding domains can be engineered with the requisite specificity for in vivo manipulations” (pg 759, col. 2, last partial paragraph). Christian goes on to describe making TALE repeat domains that target the gridlock gene of zebrafish (pg 760, col. 1, 1st partial paragraph).
Example 1 (pg 54) describes ZFNs that target PD1 or CTLA4 and confirms that they are active and capable of making a double stranded break in the target sequence. Example 1 confirms INDELS but does not confirm that any of the INDELS repressed PD1 or CTLA4 expression as required in claim 1. Example 1 does not describe integrating an exogenous nucleic acid sequence into the genome of the T-cells.
Example 2 (pg 59) describes TALENs that target PD1 or CTLA4. Example 2 confirms INDELS (pg 61, Table 6) but does not confirm that any of the INDELS repressed PD1 or CTLA4 expression as required in claim 1. Example 2 does not describe integrating an exogenous nucleic acid sequence encoding a CAR into the genome of the T-cells.
Example 3 (pg 62) contemplates generating T-cells that express a CAR and have the PD1 or CTLA4 gene knocked out. Example 3 does not teach the structure of one donor sequence containing the exogenous nucleic sequence encoding the CAR or the structure of any homology arms that flank the exogenous sequence that would allow integration of the exogenous sequence into any “selected genomic site” as required in claim 39. Example 3 does not teach the structure of a donor sequence capable of integrating the exogenous sequence into an AAVS1, CCR5, or albumin gene (claim 5) or the repressed PD1 or CTLA4 gene as broadly encompassed by claim 39.
Example 4 confirms that ZFNs that target PD1 repressed PD1 expression. Example 4 confirms INDELS using ZFNs that repressed PD1 expression (pg 62). Example 4 does not describe integrating an exogenous nucleic acid sequence into the genome of the T-cells with repressed PD1 expression.
The specification does not teach the desired effect (inactivation) occurs instead of unexpected off-target phenotypes using ZFNs.
The specification does not enable using any single ZFN or TALEN as broadly encompassed by claims 25 and 39. The specification does not correlate a pair of ZFNs or TALENs to a single ZFN or single TALEN. The specification does not teach any gRNA target sequences in any safe harbor or immuno-checkpoint gene. The specification does not teach the structure of any gRNAs that target any safe harbor or immuno-checkpoint gene. The specification does not teach ZFN or TALEN pairs to meganuclease as broadly encompassed by claims 25 and 39. Therefore, the claims should be limited to ZFN or TALEN pairs.
The specification does not enable performing the method in any species of cells as broadly encompassed by claims 25 and 39 other than human T-cells. The specification does not teach the structure of any non-human mammalian safe harbor or immuno-checkpoint genes. The specification does not teach the structure of any target points for ZFNs, TALENs, or gRNA for any non-human mammalian safe harbor or immuno-checkpoint genes. The specification does not teach any fish, amphibian, reptile, or bird genes, target sequences, or nucleases that target them. Therefore, the claims should be limited to human T-cells.
The specification does not enable performing the method in vivo as broadly encompassed by claims 25 and 39. The specification does not teach how to target a nuclease to T-cells in vivo such that enough nuclease contacts a T-cell and the desired genetic modification occurs. Therefore, the claims should be limited to isolated T-cells.
The specification does not enable performing the method in any safe harbor gene as broadly encompassed by claims 25 and 39. Safe harbor genes encompass Rosa26, AAVS1, CCR5, et al.; however, the specification does not teach the structure of any safe harbor genes, the structure of any target points for ZFNs, TALENs, or gRNA for any safe harbor genes, or the structure of any ZFNs, TALENs, or gRNA that bind any safe harbor genes. Therefore, safe harbor genes should be deleted from claims 25 and 39.
The specification does not enable performing the method in any immuno-checkpoint gene as broadly encompassed by claims 25 and 39 other than PD1 or CTLA4. The specification says the genes “include members of the extended CD28 family of receptors and their ligands as well as genes involved in co-inhibitory pathways (e.g., CTLA-4 and PD-1)” (pg 16, end of para 50) (PD1 is discussed on pg 2, para 5; CTLA4 is discussed on pg 3, para 6). However, the specification does not teach the structure of any immuno-checkpoint genes other than PD1 or CTLA4, the structure of any target points for ZFNs, TALENs, or gRNA for any immuno-checkpoint genes, or the structure of any ZFNs, TALENs, or gRNA that bind any immuno-checkpoint genes. The specification does not correlate CTLA4 to any CTLA as broadly encompassed by claims 25 and 39. Therefore, the immuno-checkpoint genes in claims 25 and 39 should be limited to PD1 or CTLA4.
The specification does not enable performing the method and obtaining T-cells that do not express the CAR as broadly encompassed by claims 25 and 39. The claims do not require that the CAR is functionally expressed in the T-cell which has no enabled use. Therefore, claims 25 and 39 should result in T-cells that functionally express the CAR.
The specification does not enable performing any genetic modification on the immuno-checkpoint gene as broadly encompassed by claims 25 and 39 other than inactivating the gene. The claim encompass integrating a CAR sequence into an immuno-checkpoint gene such that any genetic modification occurs including normal expression of the immuno-checkpoint gene. However, the specification is limited to inactivating expression of the immuno-checkpoint gene to prevent T-cell inhibition (pg 4, para 11). The specification does not contemplate leaving expression of the immuno-checkpoint gene intact while introducing the CAR sequence into the gene as broadly encompassed by claims 25 and 39. The specification does not contemplate co-expressing the CAR and the immuno-checkpoint protein from the genetically modified immuno-checkpoint gene as broadly encompassed by claims 25 and 39. Therefore, claims 25 and 39 should be limited to replacing any endogenous nucleic acid sequence encoding an immuno-checkpoint protein with a nucleic acid encoding a CAR such that the immuno-checkpoint gene is inactivated and the CAR is functionally expressed in the T-cell.
Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to perform the method of claims 25 and 39 as broadly claimed.
The specification does not enable stimulating a T-cell in claim 35, 36, 46 and 47 as part of genetically modifying the T-cell in claim 39. “Stimulating” a T-cell has nothing to do with using a nuclease to integrate a CAR sequence into the genome of a T-cell. Culturing T-cells on anti-CD23/CD38 beads in claim 47 has nothing to do with using a nuclease to integrate a CAR sequence into the genome of a T-cell as required in claim 39. Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to do so.
The specification does not enable making or using a T-cell with any “additional transgene” integrated into the T-cell genome as required in claim 33, 48, specifically a TAA-specific TCR as required in claim 34, 49. The specification does not teach any T-cells with a CAR that have a TAA-specific TCR or how to make or use such a T-cell. Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to do so.
Written Description
Claims 25-51 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The specification lacks written description for using any nuclease to insert a CAR sequence into any safe harbor or immuno-checkpoint gene of any T-cell as broadly encompassed by claims 25 and 39.
Claims 25 and 39 are recited above.
Claims 25 and 39 encompass integrating the exogenous nucleic acid sequence encoding a CAR into any safe harbor or immune-checkpoint gene including PD1 or CTLA4 using ZFNs.
Modifying a gene in cells using a ZFN was unpredictable as evidenced by Porteus (Nature Biotech., 2005, Vol. 23, No. 8, pg 967- 973), who taught ZFNs have been primarily applied to transformed mammalian cell lines that are relatively resistant to apoptotic stimuli, but not primary cells that are more sensitive to DNA damage (see page 971, 2nd col., 3re paragraph). One of the challenge of applying this method to primary cells is the delivery method, wherein the method of transformation that is suitable for cultured cell line is applicable to primary cell is unpredictable, thus remains as the area of future study (see page 972, 1st col., 3rd paragraph). Porteus taught other challenges remain in the field of developing ZFNs to stimulate gene targeting by homologous recombination. Such challenges include: 1) applicability of the ZFN approach needs to be broadened; 2) the method of delivering ZFNs and repair substrate to cells requires optimization; and 3) understanding the process of homologous recombination itself. Porteus points out that the optimization of ZFN design must address two key questions of specificity and cytotoxicity (see page971, 3re-5th paragraph).
Ramirez (Unexpected failure rates for modular assembly of engineered zinc fingers. Nature Methods, 2008, 5(5): 374-375) call into question the predictability of modularly designing zinc finger proteins to bind to nucleic acid triplets in the zinc finger DNA binding sites, and of successfully making nuclease fusion proteins of these zinc finger proteins to successfully cleave the zinc finger DNA binding sites.
Reik (US Patent Application 2008/0188000) taught the nature of the mutation made using a nuclease was unpredictable. Example 3 (pg 14-15; paragraph 159) discusses the nature of the mutation made using zinc finger binding domains 8667 and 8668. Various mutations were obtained including a 2-nucleotide deletion, an 11-nucleotide deletion, a "mixture of sequences: one of which was a duplication of four nucleotides, the other of which was a 19- nucleotide deletion" (paragraph 120). Example 3 does not teach any of the mutations caused the GR gene to be inactivated or how to use the cells having the various modifications to the GR gene.
Geurts (Science, July 24, 2009, Vol. 325, pg 433) taught a rat whose genome had a homozygous disruption in an endogenous gene made using a zinc-finger nuclease (ZFN). The ZFN had “tandem repeats” that interact with endogenous DNA in a specific manner and dimerized to cut DNA encoding GFP, IgM and Rab38 genes.
Christian (Genetics, available online 7-26-08, Vol. 186, pg 757-761) taught the barrier to the widespread adoption of ZFNs has been the challenge in engineering DNA binding specificities. Generating “the necessary reagents to modify new DNA targets” is “to some degree empirical” (based on observation/experience rather than theory or pure logic; pg 757, col. 1, 1st paragraph). “To realize the potential of TALENs for genome modification, it will be necessary to engineer them to recognize novel chromosomal DNA sequences. Randomly assembled repeat domains have been shown to bind DNA targets predicted by the cipher… …; however, custom TALEs designed to recognize new target sequences have not been reported. This is an important distinction, because the former experiments validate the cipher, whereas the latter would demonstrate that DNA binding domains can be engineered with the requisite specificity for in vivo manipulations” (pg 759, col. 2, last partial paragraph). Christian goes on to describe making TALE repeat domains that target the gridlock gene of zebrafish (pg 760, col. 1, 1st partial paragraph).
Example 1 (pg 54) describes ZFNs that target PD1 or CTLA4 and confirms that they are active and capable of making a double stranded break in the target sequence. Example 1 confirms INDELS but does not confirm that any of the INDELS repressed PD1 or CTLA4 expression as required in claim 1. Example 1 does not describe integrating an exogenous nucleic acid sequence into the genome of the T-cells.
Example 2 (pg 59) describes TALENs that target PD1 or CTLA4. Example 2 confirms INDELS (pg 61, Table 6) but does not confirm that any of the INDELS repressed PD1 or CTLA4 expression as required in claim 1. Example 2 does not describe integrating an exogenous nucleic acid sequence encoding a CAR into the genome of the T-cells.
Example 3 (pg 62) contemplates generating T-cells that express a CAR and have the PD1 or CTLA4 gene knocked out. Example 3 does not teach the structure of one donor sequence containing the exogenous nucleic sequence encoding the CAR or the structure of any homology arms that flank the exogenous sequence that would allow integration of the exogenous sequence into any “selected genomic site” as required in claim 39. Example 3 does not teach the structure of a donor sequence capable of integrating the exogenous sequence into an AAVS1, CCR5, or albumin gene (claim 5) or the repressed PD1 or CTLA4 gene as broadly encompassed by claim 39.
Example 4 confirms that ZFNs that target PD1 repressed PD1 expression. Example 4 confirms INDELS using ZFNs that repressed PD1 expression (pg 62). Example 4 does not describe integrating an exogenous nucleic acid sequence into the genome of the T-cells with repressed PD1 expression.
The specification does not teach the desired effect (inactivation) occurs instead of unexpected off-target phenotypes using ZFNs.
The specification lacks written description for using any single ZFN or TALEN as broadly encompassed by claims 25 and 39. The specification does not correlate a pair of ZFNs or TALENs to a single ZFN or single TALEN. The specification does not teach any gRNA target sequences in any safe harbor or immuno-checkpoint gene. The specification does not teach the structure of any gRNAs that target any safe harbor or immuno-checkpoint gene. The specification does not teach ZFN or TALEN pairs to meganuclease as broadly encompassed by claims 25 and 39. Therefore, the claims should be limited to ZFN or TALEN pairs.
The specification lacks written description for performing the method in any species of cells as broadly encompassed by claims 25 and 39 other than human T-cells. The specification does not teach the structure of any non-human mammalian safe harbor or immuno-checkpoint genes. The specification does not teach the structure of any target points for ZFNs, TALENs, or gRNA for any non-human mammalian safe harbor or immuno-checkpoint genes. The specification does not teach any fish, amphibian, reptile, or bird genes, target sequences, or nucleases that target them. Therefore, the claims should be limited to human T-cells.
The specification lacks written description for performing the method in vivo as broadly encompassed by claims 25 and 39. The specification does not teach how to target a nuclease to T-cells in vivo such that enough nuclease contacts a T-cell and the desired genetic modification occurs. Therefore, the claims should be limited to isolated T-cells.
The specification lacks written description for performing the method in any safe harbor gene as broadly encompassed by claims 25 and 39. Safe harbor genes encompass Rosa26, AAVS1, CCR5, et al.; however, the specification does not teach the structure of any safe harbor genes, the structure of any target points for ZFNs, TALENs, or gRNA for any safe harbor genes, or the structure of any ZFNs, TALENs, or gRNA that bind any safe harbor genes. Therefore, safe harbor genes should be deleted from claims 25 and 39.
The specification lacks written description for performing the method in any immuno-checkpoint gene as broadly encompassed by claims 25 and 39 other than PD1 or CTLA4. The specification says the genes “include members of the extended CD28 family of receptors and their ligands as well as genes involved in co-inhibitory pathways (e.g., CTLA-4 and PD-1)” (pg 16, end of para 50) (PD1 is discussed on pg 2, para 5; CTLA4 is discussed on pg 3, para 6). However, the specification does not teach the structure of any immuno-checkpoint genes other than PD1 or CTLA4, the structure of any target points for ZFNs, TALENs, or gRNA for any immuno-checkpoint genes, or the structure of any ZFNs, TALENs, or gRNA that bind any immuno-checkpoint genes. The specification does not correlate CTLA4 to any CTLA as broadly encompassed by claim 39. Therefore, the immuno-checkpoint genes in claims 25 and 39 should be limited to PD1 or CTLA4.
The specification lacks written description for performing the method and obtaining T-cells that do not express the CAR as broadly encompassed by claims 25 and 39. The claims do not require that the CAR is functionally expressed in the T-cell which has no enabled use. Therefore, claims 25 and 39 should result in T-cells that functionally express the CAR.
The specification lacks written description for any genetic modification on the immuno-checkpoint gene as broadly encompassed by claims 25 and 39 other than inactivating the gene. The claim encompass integrating a CAR sequence into an immuno-checkpoint gene such that any genetic modification occurs including normal expression of the immuno-checkpoint gene. However, the specification is limited to inactivating expression of the immuno-checkpoint gene to prevent T-cell inhibition (pg 4, para 11). The specification does not contemplate leaving expression of the immuno-checkpoint gene intact while introducing the CAR sequence into the gene as broadly encompassed by claims 25 and 39. The specification does not contemplate co-expressing the CAR and the immuno-checkpoint protein from the genetically modified immuno-checkpoint gene as broadly encompassed by claims 25 and 39. Therefore, claims 25 and 39 should be limited to replacing any endogenous nucleic acid sequence encoding an immuno-checkpoint protein with a nucleic acid encoding a CAR such that the immuno-checkpoint gene is inactivated and the CAR is functionally expressed in the T-cell.
Accordingly, the method of claims 25 and 39 lacks written description as broadly claimed.
The specification lacks written description for stimulating a T-cell in claim 35, 36, 46 and 47 as part of genetically modifying the T-cell in claim 39. “Stimulating” a T-cell has nothing to do with using a nuclease to integrate a CAR sequence into the genome of a T-cell. Culturing T-cells on anti-CD23/CD38 beads in claim 47 has nothing to do with using a nuclease to integrate a CAR sequence into the genome of a T-cell as required in claim 39. Accordingly, the concept lacks written description.
The specification lacks written description for a T-cell with any “additional transgene” integrated into the T-cell genome as required in claim 33, 48, specifically a TAA-specific TCR as required in claim 34, 49. The specification does not teach any T-cells with a CAR that have a TAA-specific TCR or how to make or use such a T-cell. Accordingly, the concept lacks written description.
Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 35, 36, 46, 47 are rejected 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 which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The concept of stimulating a T-cell in claim 35, 36, 46 and 47 as part of genetically modifying the T-cell in claim 25 or 39 makes the claims indefinite. “Stimulating” a T-cell has nothing to do with using a nuclease to integrate a CAR sequence into the genome of a T-cell. Culturing T-cells on anti-CD23/CD38 beads in claim 36 or 47 has nothing to do with using a nuclease to integrate a CAR sequence into the genome of a T-cell as required in claim 25 or 39. Accordingly, the step makes the claims indefinite.
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 pre-AIA 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 –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
Claims 25-33, 35-43, 46-48 are rejected under pre-AIA 35 U.S.C. 102b as being anticipated by Cost (2013/0122591).
Cost taught isolated T-cells with a disruption in an endogenous safe harbor gene made by TALEN pairs and an exogenous donor sequence encoding a CAR inserted into the disruption (para 7, “the transgene may be inserted into a specific "safe harbor" location in the genome”; para 13, 22, 24; “insertion of a chimeric antigen receptor (CAR) or insertion of one or more T cell receptor gene(s) into a T-cell ex vivo”; claims 6, 8, 13, 25). This is equivalent to claims 25, 29, 30, 39.
Claims 26, 27, 37, 38, 40 have been included because they do not exclude targeting a safe harbor gene. They further limit the immune-checkpoint gene and still encompass targeting a safe harbor gene. In particular, claim 37 is a product-by-process and does not further limit the structure or function of the T-cell or say that it has a genetically modified checkpoint gene. Further limiting the nuclease in claim 37 used to modify the T-cell of claim 25 bears no patentable weight in distinguishing the T-cell of Cost from the T-cell claimed.
Cost taught using a plasmid or viral vector as required in claim 41 (paragraphs 18-19 and throughout).
Cost taught the nuclease is introduced as mRNA as required in claim 42 (para 30).
The T-cells of Cost are inherently CD4+ or CD8+ as required in claim 28 43.
The CAR of Cost inherently MUST comprise a signaling domain of a TCR as required in claims 31, 44 because CARs are defined as having a signaling domain of a TCR.
The CAR of Cost inherently MUST comprise a scFV specificity domain as required in claims 32, 45 because CARs are defined as having a scFV specificity domain.
Claims 35, 36, 46, 47 has been included because “stimulating” T-cells has nothing to do with the genetic modification of T-cells as required in claim 39.
Additional sequences can be inserted using additional nucleases as required in claim 33, 48 (para 68, 72 of Cost).
Claim Rejections - 35 USC § 103
A) Claims 25-33, 35-43, 46-51 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Cost (2013/0122591) in view of Wood (2011/0033884), Weber (Seminars in Oncology, Oct. 2010, Vol. 37, No. 5, pg 430-439), Turtle (Curr. Opin. Immunol., 2012, Available online July 18, 2012, Vol. 24, pg 633-639) and GenBank #: AF363458.1 (2001).
The teachings of Cost are described above.
Cost did not teach the gene was the human PD1 gene as required in claims 26, 27, 50 and 51.
However, it was well known to target the human PD1 gene for genetic modification in mammalian cells, specifically for insertions of exogenous sequences as described by Wood (pg 22, para 204, last 10 lines “homologous recombinant animal”; pg 23, para 206, creating a homologous recombinant animal to “functionally disrupt” the PD1 gene; para 206 “The B7-4 or PD-1 gene can be a human gene (e.g., the SEQ ID NO:1, 3, 10, or 11)”). The human PD1 gene described by GenBank #: AF363458.1 in 2002 has the targeting sequences of SEQ ID NO: 33 starting at nucleotide 6922. SEQ ID NO: 21-33 are functional equivalents.
Thus it would have been obvious to those of ordinary skill in the art at the time of filing to make a T-cell with an inactivated safe harbor gene inserted with an exogenous sequence encoding a CAR as described by Cost wherein the safe harbor gene was PD1 as described by Wood. Those of ordinary skill in the art at the time of filing would have been motivated to replace the safe harbor gene of Cost with the safe harbor PD1 gene described by Wood because Weber taught PD1 was a checkpoint protein, and that PD1 inactivation would be therapeutically effective in cancer patients (abstract). Those of ordinary skill in the art at the time of filing would have been motivated to combine the T-cells transfected with vectors encoding CARs containing scFv with inhibiting PD1 checkpoint because Turtle suggests combining T-cells transfected with vectors encoding CAR while inhibiting CTLA4 or PD1 checkpoints (last paragraph).
Dependent claims are discussed above.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
B) Claim 46 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Cost (2013/0122591) in view of Wood (2011/0033884), Weber (Seminars in Oncology, Oct. 2010, Vol. 37, No. 5, pg 430-439), and Turtle (Curr. Opin. Immunol., 2012, Available online July 18, 2012, Vol. 24, pg 633-639), and GenBank #: AF363458.1 (2002) as applied to claims 25-33, 35-43, 46-48 and further in view of 20110158957.
The combined teachings of Cost, Wood, Weber, Turtle, and GenBank #: AF363458.1 taught T-cells whose genome comprises a replacement of a PD1 gene with a sequence encoding a CAR.
This rejection assumes the combined teachings of Cost, Wood, Weber, Turtle, and GenBank #: AF363458.1 did not teach the T-cells were stimulated as required in claim 46.
However, doing so was well known as described in paragraphs 9-12, 26, 27, 125, 129 of 20110158957 acknowledged by applicants in paragraph 18.
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make T-cells whose genome comprises a replacement of a PD1 gene with a sequence encoding a CAR as described by the combined teachings of Cost, Wood, Weber, Turtle, and GenBank #: AF363458.1 and stimulating the T-cells using anti-CD23/CD38 beads as described in ‘957. Those of ordinary skill in the art at the time of filing would have been motivated to stimulate them to activate their T-cell functions.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
C) Claims 46 and 47 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Cost (2013/0122591) in view of Wood (2011/0033884), Weber (Seminars in Oncology, Oct. 2010, Vol. 37, No. 5, pg 430-439), Turtle (Curr. Opin. Immunol., 2012, Available online July 18, 2012, Vol. 24, pg 633-639), and GenBank #: AF363458.1 (2006) as applied to claims 25-33, 35-43, 46-48 and further in view of 2008031195.
The combined teachings of Cost, Wood, Weber, Turtle, and GenBank #: AF363458.1 taught T-cells whose genome comprises a replacement of a PD1 gene with a sequence encoding a CAR.
The combined teachings of Cost, Wood, Weber, Turtle, and GenBank #: AF363458.1 did not teach the T-cells were stimulated, specifically using anti-CD28/CD3 beads, as required in claims 46 and 47.
However, doing so with anti-CD28/CD3 beads was well known as described in 20080311095 acknowledged by applicants in paragraph 20.
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make T-cells whose genome comprises a replacement of a PD1 gene with a sequence encoding a CAR as described by the combined teachings of Cost, Wood, Weber, Turtle, and GenBank #: AF363458.1 and stimulating them with beads as described in ‘095. Those of ordinary skill in the art at the time of filing would have been motivated to stimulate them to activate their T-cell functions.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
D) Claims 39-43, 46-48, 50 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Waterhouse (5714667) in view of Cost (2013/0122591) and GenBank #: DQ357942.1 (2006).
Waterhouse taught mouse T-cells with an inactivated immuno-checkpoint CTLA4 gene (description of Fig. 3; All examples).
Waterhouse did not teach integrating a CAR sequence into the inactivated CTL4 gene as encompassed by claims 25 and 39.
However, Cost taught isolated T-cells with a disruption in an endogenous gene made by TALEN pairs and an exogenous donor sequence encoding a CAR inserted into the disruption (para 13, 22, 24; “insertion of a chimeric antigen receptor (CAR) or insertion of one or more T cell receptor gene(s) into a T-cell ex vivo”; claims 6, 8, 13, 25).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a T-cell with an inactivated immuno-checkpoint CTLA4 gene as described by Waterhouse and integrating an exogenous CAR sequence into the gene as described by Cost. Those of ordinary skill in the art at the time of filing would have been motivated to have the T-cell express a CAR to impart therapeutic value to the T-cells of Waterhouse.
Dependent claims have been included for reasons described by Cost and discussed above.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 25-51 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 11236175. Although the claims at issue are not identical, they are not patentably distinct from each other because the ZFNs used to make the T-cell in ‘175 could have been claimed in this case and because they could have been excluded in the claims of ‘175.
Claims 25-51 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 9597357. Although the claims at issue are not identical, they are not patentably distinct from each other because the genetic modification in the T-cell in ‘357 could have been claimed in this case and because they could have been excluded in the claims of ‘357.
Conclusion
No claim is allowed.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
Prosecution Insights