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 .
Examiner’s Note: Claim 96 is being interpreted to include the conjunction “or” in order to give the claim its broadest reasonable interpretation. This interpretation allows for each element to be considered individually or in any combination with the others. As a result, the claim will be interpreted to cover any embodiment that includes one or more of the listed items allowing for the full scope of the claimed invention to be considered during the examination.
Status of Claims
Claims 1, 9, 37-39, 47, 65, 75-76, 96, 116-117, 149, 169, 213, and 310-313 are pending.
Priority
Claims 1, 9, 37-39, 47, 65, 75-76, 96, 116-117, 149, 169, 213, and 310-313 are a 371 of PCT/US 2022/074873 filed on August 11, 2022, which has priority to PRO 63/353,548 filed on June 17, 2022, and to PRO 63/232,163 filed on August 11, 2021.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on November 26, 2024, was filed before the mailing of the First Office Action on July 6, 2026. The Non-Patent Literature is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
Claim Objections
Claims 1 and 37 are objected for the following reasons:
Claim 1 on line 7 recites “wherein the change in expression is relative a cell” should read as “wherein the change in expression is relative to a cell”.
Claim 37 on line 7 recites “wherein the change in expression is relative a cell” should read as “wherein the change in expression is relative to a cell”.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 96 is 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.
Claim 96 recites the generic language “any of (i)-(iv) above further comprising additional edits that increase or decrease expression of target” as it relates to an engineered cell that exhibits a reduction in expression of certain cell markers while other cell markers are increased.
The specification provides antecedent basis for “any of (i)-(iv) above further comprising additional edits that increase or decrease expression of target” [¶ 100].
Applicant’s specification recites “additional edits” twice at paragraphs [0100] and [0185]. In paragraph [0479], the specification discusses modifications to MICA. In paragraph [0484], the specification discusses the various modifications of MICB. In paragraph [0489], the specification discusses various modification associated with MHC class I molecules. In paragraph [0501], the specification recites various modifications related to MHC class II molecules. In paragraph [0529], the specification discusses modifications where one or more polynucleotides are expressed in a cell. This includes exogenous polynucleotides where the engineered cell can express up to 10 or more overexpressed polynucleotides [Id.] In paragraph [0535], the specification discusses the expression or overexpression of tolerogenic factors such as CD47. In paragraph [0578] discusses engineered cells that have been modified to express or overexpress chimeric antigen receptor and associated domains [¶ 0609, 0610]. However, the specification does not reasonably convey to a person of ordinary skill in the art that Applicant was in possession of the full scope of the claimed limitation. Although the specification describes certain exemplary gene edits and specific targets, the claim encompasses any additional edit capable of increasing or decreasing expression of any target. Furthermore, there is no representative number, structural features, or common characteristics sufficient to demonstrate possession of such a broad genus being claimed. Although techniques for increasing or decreasing gene expression are generally known in the art, the specification does not provide sufficient guidance, representative examples, or identifying characteristics to allow a person of ordinary skill in the art to reasonably understand the scope or be able to quantify what additional elements are being claimed or would qualify as edits under the claim language.
Given the generic scope of “any of (i)-(iv) above further comprising additional edits that increase or decrease expression of target”, and the absence of teaching what additional edits qualify, the Artisan would not understand Applicant to be in possession of the generic scope of “any of (i)-(iv) above further comprising additional edits that increase or decrease expression of target”.
Claim Rejections - 35 USC § 112
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.
Claim 96 and 116 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.
Claim 96 recites that the engineered cell comprises modifications according to items (i)-(iv). However, claim 96 fails to define the relationship among the recited items. There is no conjunctive or disjunctive connector between items (iv) and (v). Furthermore, item (v) recites “any of (i)-(iv) above further comprising additional edits that increase or decrease expression of a target”. As a result, it is unclear whether item (v) is required in combination with items (i)-(iv), is an alternative to items (i)-(iv), or is an optional limitation applicable to one or more items (i)-(iv). Given this, the claim scope varies depending on what interpretation is adopted resulting in a person of ordinary skill in the art to not be able to determine metes and bounds of the claim.
Claim 116 recites the limitation "the human" in Line 2. There is insufficient antecedent basis for this limitation in the claim.
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.
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, 9, 37-39, 47, 65, 75-76, 96, 116-117, 149, 169, 213, and 310-313 are rejected as being unpatentable over Johannesson et al. [WO 2021 072302 A1], in view of Bhoumik et al. [WO 2019 014351 A2], in view of Tsubaki et al. [Thioredoxin-interacting protein (TXNIP) with focus on brain and neurodegenerative diseases, International Journal of Molecular Sciences, 2020], in view of Zwirner et al. [Identification of MICA as a new polymorphic alloantigen recognized by antibodies in sera of organ transplant recipients, Human Immunology, 2000].
Regarding claim 1, Johannesson et al. teaches an engineered cell with reduced expression of MHC class I chain-related protein A (MICA) and/or a MHC class I chain-related protein B (MICB) [¶ 0054, 0018]. Johannesson et al. further teaches an increase in expression of CD47, i.e. a tolerogenic factor [¶ 00135]. However, Johannesson et al. does not teach the reduced expression of major histocompatibility complex (MHC) class 1 molecules and/or MHC class II molecules where the reduced expression is related to reducing gene activity in B2M and/or CIITA, respectively.
For these limitations, Bhoumik et al. discloses that disruption, deletion, modification, and/or inhibition of B2M results in deficiency in all of HLA class I surface expression and function, i.e. MHC class I molecules [¶ 0007]. Bhoumik et al. further discusses pluripotent stem cells comprising modulated expression of NK cell activating ligands compared to wild-type human pluripotent stem cells where the pluripotent stem cells do not express CIITA which would cause a reduction in MHC class II molecules [¶ 00137]. Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Johannesson et al. where stem cells were engineered in attempt to avoid immune detection with the teachings of Bhoumik et al. where pluripotent stem cells were also engineered in order to create universal donor cells that would be capable of overcoming both the innate and adaptive immune response of the host. Given this, there is a reasonable expectation of success that a person of ordinary skill in the art would combine Johannesson et al. with the further teachings of Bhoumik et al. allowing for cells to be engineered with reduced expression of MICA and/or MICB, and where the MHC class I and II molecules were also reduced by modifying both genes B2M and CIITA while modifying the cell to overexpress CD47 given that these factors are known in the art for overcoming innate immune signaling that further prevents the adaptive immune response from being triggered.
For claim 9 where the MHC class I molecule is reduced by inactivation or disruption of the B2M coding sequence, and the MHC class II molecule is reduced by the same method targeting the CIITA coding sequence, Bhoumik et al. teaches the reduction of expression of both MHC class I and II molecules by disrupting and/or not encoding for B2M or CIITA coding sequences [¶ 00136, 00137, and 007].
For claim 37 where there is a reduction in MICA and/or MICB with an increase in expression of tolerogenic factors such as CD47 where the change in expression is relative to the same cell type that does not include the same modifications, Johannesson et al. discloses both the reduction of MICA and/or MICB with an overexpression of CD47 where the modifications are compared relative to expression in wild-type stem cells [¶ 0018, 0054, 00135, and 0009].
For claim 38 where the engineered cell has a reduction in MHC class I and II molecules and overexpression of tolerogenic factors such as CD47, the same analysis is applied here as it is applied to claim 1 [Johannesson et al. ¶ 0051, 00135, & Bhoumik et al. ¶ 007, 004].
For claim 39 where the engineered cell comprises a knockout of MHC class I molecules, MICA and/or MICB, and TXNIP, a knock-in of PDL1 and HLAE, Johannesson discloses a knock-in of both PDL1 and HLA-E [¶ 0011, 0012], Johannesson further discloses nucleofected clones that contained a frameshift mutation that resulted in lack of expression of both MICA and MICB [¶ 00118].
For claim 47 where inactivation or disruption of both alleles of the MICA gene or inactivation or disruption of all MICA coding sequences, Johannesson teaches frameshift mutations in all 4 alleles leading to no expression of MICA [¶ 00118].
For claim 65 where the inactivation or disruption takes place on the MICB gene or coding sequence, Johannesson, again, teaches a frameshift mutation that results in all 4 alleles of MICA/MICB not being expressed [ ¶ 00118].
For claim 75 where the engineered cell contains modifications that result in a reduction of expression of NLRC5, Bhoumik et al. discloses a modified stem cell that does not express NLRC5 [¶ 00137].
For claim 76 where an engineered cell further contains modifications of one or more tolerogenic factors that include CD47, CD46, CD55, etc., Johannesson et al. teaches the increased expression of CD 47 as well as other listed factors [¶ 00135, 00159].
For claim 96 where items (i)-(v) include variations of the engineered cell of claim 38, for item (i), as stated in claim 1, Bhoumik et al teaches the reduction of the expression of either or both of MHC class I and II molecules [¶ 007, 004]. Additionally, Johannesson et al. discloses the increased expression of CD47 [¶ 00135].
For the claim 96 limitation (ii), Bhoumik et al. teaches a modified cell with reduced expression of MHC class I and II molecules [¶ 007, 004], With Johannesson et al. disclosing a reduction in expression of MICA and/or MICB [¶ 00118, 0054] along with increased expression of CD47 [¶ 00135], along with an increase of expression of CD46, CD55, CD59, and CR1 [¶ 00159]. Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Johannesson et al. where stem cells were engineered in attempt to avoid immune detection with the teachings of Bhoumik et al. where pluripotent stem cells were also engineered in order to create universal donor cells that would be capable of overcoming both the innate and adaptive immune response of the host. Given this, there is a reasonable expectation of success that a person of ordinary skill in the art would combine Johannesson et al. with the further teachings of Bhoumik et al. allowing for cells to be engineered with reduced expression of MICA and/or MICB, and where the MHC class I and II molecules were also reduced by modifying both genes B2M and CIITA while modifying the cell to overexpress CD47, as well as increased expression of CD46 and others, given that these factors are known in the art for overcoming innate immune signaling that further prevents the adaptive immune response from being triggered.
For the claim limitation (iii), Bhoumik et al. teaches reduced expression of MHC class I molecules [¶ 007, 004] with Johannesson et al. teaching a reduction and/or inhibition of MICA and/or MICB [¶ 00118, 0054], with an increase in PDL1 and HLA-E versus stem cells without the modification [¶ 0011, 0012]. Additionally, Tsubaki et al. teaches that TXNIP is a key negative regulator of the thioredoxin antoxidant system and is upregulated under conditions of oxidative stress which contributes to increased reactive oxygen species, inflammation, and cellular dysfunction. Furthermore, Tsubaki et al. states reducing TXNIP expression restores thioredoxin function which leads to decreased oxidative stress. Therefore, it would have been prima facie obvious to a person of ordinary skill in the art to modify the methods and systems of Johannesson et al. and Bhoumik et al. that discuss modifying cells in order to avoid or reduce the risk of activating the innate immune system and thereby avoiding the adaptive immune system with the further teachings of Tsubaki et la. that teaches a reduction of TXNIP would further insulate the modified cell against oxidative stress. Given this, there is a reasonable expectation of success that a person of ordinary skill in the art could combine the teachings of both Johannesson et al. and Bhoumik et al. with the additional teachings of Tsubaki et al. in order to further modify cells that are capable of avoiding or mitigating possible activation of a host’s innate immune response or any adverse effect related to the innate immune system or the adaptive immune system.
For claim 116 where the modified cell is derived from a human, Johannesson et al. discloses that the pluripotent stem cells were derived from a human [¶ 0084].
For claim 117 where the engineered cell is derived from a differentiated cell derived from a pluripotent stem cell or a progeny thereof, Johannesson et al. teaches that modified stem cell can be an induced pluripotent stem cell [¶ 0084].
For claim 149 where a composition comprising a population of engineered primary beta islet cells includes inactivation of MICA and/or MICB genes, a transgene comprising an exogenous polynucleotide encoding CD47, and inactivation and/or disruption of all alleles of a B2M gene, Johannesson et al. teaches that the modified cells can be primary beta islet cells [¶ 0042, 0016] where the MICA/MICB alleles are inactivated and/or disrupted all alleles [¶ 0054, 00118], and that an increase in CD47 is by an exogenous polynucleotide [¶ 00135]. However, Johannesson et al. does not teach the inactivation or disruption of all alleles in B2M. For this, Bhoumik et al. discloses inactivation and/or disruption of B2M [¶ 007].
For claim 169 where an engineered cell has a reduction and/or eliminating the expression of MHC class I and class II molecules, an increase in tolerogenic factors, and a reduction of MICA and MICB in the source cell, Bhoumik et al., again, discloses reduction/elimination of MHC class I and II molecules by inhibiting or not expressing B2M and CIITA [¶ 007, 004]. And for elements (b) and (c), Johannesson et al. teaches increased expression of one or more tolerogenic factors while reducing the expression of MICA/MICB [¶ 00135, 0054]. Additionally please see the rational for prima facie obviousness under claim 1.
For claim 213 where a method of treatment using an allogeneic therapy where the engineered cell of claim 1 is administered and the subject is screened for the presence of anti-MICA antibodies and/or anti-MICB antibodies, Zwirner et al. teaches the screening of transplant patients in order to determine the presence of specific antibodies that are capable of targeting MICA [Abstract]. This is because MICA is an HLA-related polymorphic gene product that is recognized by a subpopulation of T cells found in the intestinal tract resulting in the activation of certain natural killer cells [Abstract].
For claims 310 and 311 where the modification of the engineered cells includes inactivation of both alleles of the MICA/MICB gene or disruption of the MICA/MICB coding sequence, Johannesson et al. discloses a frameshift mutation in all 4 alleles of MICA and MICB that led to MICA and MICB not being expressed [¶ 0054, 00118].
For claim 312 where the engineered cell is derived from a human, Bhoumik et al. discloses the modified cells are derived from a human [¶ 007].
For claim 313 where the engineered cell is derived from a pluripotent stem cell or a progeny thereof, Johannesson et al. teaches that modified stem cells can be derived from either a induced pluripotent stem cell or embryonic stem cell [¶ 0084].
Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Johannesson et al. and Broumik et al. where both modified stem cells using known knock-in and knock-out techniques to modify the stem cells in order to improve the cell survivability when administered to a patient in order to avoid or minimize activating the innate immune response and subsequently the adaptive immune response with the additional teachings of Tsubaki et al. where they disclosed that reduction in TXNIP leads to less chance of disruption of cellular processes related to oxidative stress. Furthermore, it would also have been prima facie obvious to a person of ordinary skill, in addition to the above teachings, to recognize the teachings and methods of Zwirner et al. where it was disclosed that certain groups of antibodies are capable of targeting MICA, and that by screening patients for the presence of these antibodies allows a clinician whether to administer or not to administer the engineered cell composition. Given this, there is a reasonable expectation of success that a person of ordinary skill would be able to combine the teachings of Johannesson et al. with the teachings of Broumik et al. in order to develop numerous iterations of an engineered cell where the cells could posses a reduction in MICA/MICB expression either partially or completely, increase in expression of tolerogenic factors, such as CD47, while also inhibiting or disrupting MHC class I and II proteins with the additional teachings of Tsubaki et al. that disclosed the benefits of reducing the expression of TXNIP resulting in the modified cells being better at adapting to oxidative stress with the further teachings of Zwirner that discloses that some patients may exhibit antibodies capable of recognizing MICA/MICB where this would allow a clinician to better determine the best approach at deciding whether the claimed composition would be therapeutically effective.
The Supreme court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) emphasis added.
In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton.").
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims allowed.
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/JOHN DAVID MOORE/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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