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 .
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 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.
Priority
The instant application, filed 11/16/2023, is a 371 filing of PCT/US22/30394, filed 05/20/2022, and claims domestic benefit to US provisional applications 63/255,803, filed 10/14/2021, and 63/190,685, filed 05/19/2021.
Status of Claims/Application
Applicant’s preliminary amendment of 07/09/2024 is acknowledged. Claims 1-188 are cancelled and claims 189-212 are new. Claims 189-212 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 04/01/2024 and 09/26/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
The instant specification contains nucleotide and amino acid sequences throughout without a filed "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”
Additionally, the specification recites nucleic acid sequences that are not identified with an appropriate SEQ ID NO. For instance, see the nucleotides in Tables 1B, 1C, and 1D spanning pages 57-237, all of which have more than 10 nucleic acids, but are not associated with an appropriate SEQ ID NO.
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification Objection
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Page 310, paragraph [00497], contains the following hyperlinks comprising non top-level domain browser executable code (bolded for clarity):
biorxiv.org/content/early/2017/04/02/123158;
doi.org/10.1101/123158;
www.nature. com/nature/journal/v499/n745 8/full/nature 12343.html;
science.sciencemag.org/content/early/2017/04/05/science.aam9361; and
doi.org/10.1101/122697
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 189-191, 194-195, 198-200, and 205-212 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/018620 A1 (Schrepfer, S., and T. Deuse) 23 Jan 2020 in view of Kim, Y.H., et al (2015) Rh D blood group conversion using transcription activator-like effector nucleases Nature Communications 6(7451); 1-13.
WO’620 teaches universally acceptable “off the shelf” hypoimmune pluripotent (HIP) cells and hypoimmune chimeric antigen receptor T (CAR-T) cells derived from the HIP cells. The engineered cells can be administered to subjects as an adoptive cell-based immunotherapy to treat cancer (abstract). WO’620 further teaches a method of treating a patient with cancer by administering a composition comprising a therapeutically effective amount of the isolated CAR-T cells disclosed. In some embodiments, the composition further comprises a therapeutically effective carrier (page 4, [0030]).
WO’620 relates to adoptive immunotherapy and CAR expressing cells, e.g., T cells, that have been differentiated from hypoimmunogenic pluripotent (HIP) stem cells comprising a nucleic acid encoding the CAR. The engineered HIP cells are genetically modified to be homozygous null for the beta-2 microglobulin (B2M) gene, homozygous null for the class II transactivator (CIITA) gene, and to overexpress CD47 (page 1, [0002]).
WO’620 teaches methods of modifying nucleic acid sequences within cells or cell-free conditions to generate both pluripotent cells and HIP cells. Exemplary technologies include homologous recombination, knock-in, ZFNs, TALENs, meganucleaes, CRISPR/Cas9 and other site-specific nuclease technologies (page 20, [00103]). In general, these techniques can be used individually or in combination. For example, in the generation of HIP cells, CRISPR/Cas may be used to reduce expression of active B2M and/or CIITA protein in the engineered cells and viral techniques, e.g., retrovirus, lentivirus, and adeno-associated virus, can be used to knock in the CD47 functionality. Also, as will be appreciated by those in the art, although one embodiment sequentially uses a CRISPR/Cas step to knock out B2M, followed by a CRISPR/Cas step to knock out CIITA, with a final step of lentiviral knock in of the CD47 functionality, these genes can be manipulated in different orders and using different technologies (page 20, [00105]).
WO’620 teaches that the hypoimmunogenic CAR T cells lack MHC I function or HLA I function. For instance, the cells have reduced expression or lack expression of HLA-A protein, HLA-B protein, and HLA-C protein. In particular cases, the genes encoding the proteins are inactivated. In certain cases, the cells have reduced or lack expression of β-2 microglobulin protein, or have a genetic modification that inactivates the gene encoding β-2 microglobulin protein. Such cells can be differentiated from hypoimmunogenic pluripotent cells that lack HLA-I function. In some embodiments the cells possess a genetic modification that inactivates the gene encoding β-2 microglobulin (page 36, [00179]).
WO’620 further teaches that the cells lack MHC II function or HLA-II function. In some instances, the hypoimmunogenic CAR-T cells have reduced expression or lack expression of HLA-DP protein, HLA-DR protein, and HLA-DQ protein. The hypoimmunogenic CAR T cells may possess genetic modifications to inactivate the genes encoding these proteins. In some embodiments, the cells have reduced or lack expression of CIITA. Such cells possess a modification that inactivates the gene encoding CIITA. Such hypoimmunogenic CAR T cells can be differentiated from hypoimmunogenic pluripotent cells that lack HLA-II function. In some embodiments the cells possess a genetic modification that inactivates the gene encoding CIITA (page 36, [00180]).
WO’620 further teaches that the cells have increased expression of CD47 compared to a wild-type, native T cell, or native pluripotent cell. The increased expression of CD47 may result from a genetic modification to an endogenous CD47 genes or result from expression of an exogenous CD47 gene, e.g., an exogenous nucleic acid encoding CD47 (pages 36-37, [00181]). WO’620 teaches that the cells have increased expression of CD47, known as the “don’t eat me” protein that suppresses phagocytic innate immune surveillance and elimination of HLA-devoid cells. Surprisingly, the same tolerogenic mechanisms that prevent rejection of the fetus during pregnancy, also allow the HIP cells of the invention to escape rejection and facilitate long-term survival and engraftment of these cells after allogenic transplantation (page 8, [0051]).
WO’620 further teaches that the CAR can comprise an extracellular domain, a transmembrane domain, and an intracellular signaling domain (page 2, [0007]). WO’620 also teaches embodiments in which the CAR comprises two signaling domains (page 2, [0009]). WO’620 teaches that the CAR extracellular domain is a single chain variable fragment (scFv) and binds to an antigen selected from the group consisting of CD19, CD20, CD22, CD38, CD123, CS1, CD171, BCMA, MUC16, ROR1, and WT1 (page 2, [0008]).
WO’620 teaches that the fetomaternal tolerance can be introduced with as little as three genetic modifications (as compared to the starting iPSCs, e.g., human iPSCs) including two reductions in activity (“knock outs”) and one increase in activity (a “knock in”) (page 8, [0052]).
WO’620 further teaches that the HIP cells do not give rise to an immune response. Thus, hypo-immunogenic or hypoimmune refers to a significantly reduced or eliminated immune response when compared to the immune response of a parental, i.e., wild type, cell prior to immunoengineering (page 11, [0068]). The HIP cells exhibit pluripotency but do not result in a host immune response when transplanted into an allogeneic host such as a human patient, either as the HIP cells or as the differentiated products of the HIP cells (page 32, [00164]). WO’620 teaches that, once the HIP cells have been generated, they can be assayed for their hypoimmunogenicity and/or retention of pluripotency as described. For example, they are assayed using a number of techniques including transplantation into allogenic hosts and monitoring for HIP cell growth that escape the host immune system. Similarly, T cell and/or B cell response of the host animal to the HIP can be analyzed to confirm that the HIP cells do not cause an immune reaction in the host animal. Alternatively, the cells can be assayed for their ability to avoid innate immune response, e.g., NK cell killing (page 32, [00162]).
WO’620 also exemplifies the generation of human induced pluripotent stem cells from CD34+ cord blood (Example 2, starting on page 45, [0219]) as well as the generation of T cells from HIP cells (Example 4, starting on page 50, [00236]).
WO’620 teaches that, as known in the art, iPSCs are made from non-pluripotent cells such as CD34+ cord blood cells, fibroblasts, etc. by transiently expressing reprogramming factors (page 26, [00127]).
WO’620, does not disclose that the cells include one or more genetic modifications to reduce expression of RhD antigen relative to reference cells of the same cell type and that the patient is RhD sensitized.
Kim teaches that group O D-negative blood cells are universal donors in transfusion medicine and methods for converting other blood groups into this universal donor group have been researched. However, conversion of D-positive cells to D-negative had yet to be achieved. The RhD blood group is determined by the RHD gene, which encodes a 12-transmembrain domain protein. Kim teaches the conversion of Rh D-positive erythroid progenitor cells into D-negative cells using RHD-targeting transcription activator like effector nucleases (TALENs). After transfection of TALEN-encoding plasmids, RHD-knockout clones are obtained. Erythroid-lineage cells differentiated from these knockout erythroid progenitor cells do not agglutinate in the presence of anti-D reagents and do not express D antigen, as assessed using flow cytometry. Kim teaches that the programmable nuclease induced blood group conversion opens avenues for compatible donor cell generation in transfusion medicine (abstract).
Kim teaches that the Rh D blood system was discovered in 1940 and, since then, a number of Rh antigens have been identified. D is the most immunogenic and clinically important among 50 well-defined antigens in the Rh system. D antigenicity is determined by the RHD protein, a 12 transmembrane domain protein encoded by RHD, a gene on chromosome 1. Roughly 85%, 95%, and more than 99.5% of Caucasians, black Africans, and east Asians are D positive, respectively (page 2, left column, paragraph 2).
The D antigen poses a danger for Rh D-negative people. Because those who are Rh D-negative do not have naturally occurring antibodies against the D antigen, adverse effects may not occur when an Rh-D negative person is first exposed to Rh D-positive cells through blood transfusion or giving birth to an Rh D positive baby. After such initial exposure, however, an Rh D-negative person can develop anti-Rh D antibodies which can induce immune response against Rh D positive cells. When the Rh D negative person is again exposed to Rh D positive cells these immune responses can cause adverse effects including haemolysis. The ability to convert Rh D positive into Rh D negative cells could provide a starting point for development of a potential therapeutic modality for these problems (page 2, left column, paragraph 2). It is noted that, as discussed above, Rh D negative persons can be exposed to Rh D positive cells through blood transfusions. As the person is Rh D negative and the transfused blood is Rh D positive, an ordinarily skilled artisan would reasonably identify that the blood transfusion is allogeneic as it is from a person who is Rh D positive.
Kim teaches that programmable nucleases, which include zinc-finger nucleases (ZFNs), transcription activator like effector nucleases (TALENs), and RNA guided engineered nucleases (RGENs), enable targeted genetic modifications in cells and organisms. It has previously been shown that ZFNs, TALENs, and RGENs can be used to disrupt protein coding genes in various human cells (paragraph bridging columns, page 2).
Kim demonstrates disruption of RHD in Rh D positive human erythroid progenitor cells using two different pairs of TALENs. RHD-knockout erythroid progenitor cells were obtained and gave rise to erythroid linage cells that show an Rh D negative cell phenotype in flow cytometry and agglutination tests. The data provides evidence that blood group conversion can be achieved using programmable nuclease based gene editing (page 2, right column, paragraph 1).
Kim used TALENs to make RHD knockout cells from Rh D positive erythroid progenitor cells. The source of progenitor cells was the HiDEP-1 cell line, which is derived from induced pluripotent stem cells generated from fibroblasts of an Rh D positive (DD) donor (page 2, right column, generation of clones containing RHD mutations). Kim also studied RHD mRNA clones in HiDEP-1 cells as well as erythroid cells differentiated from primary human cord blood CD34+ cells (paragraph bridging pages 4 and 6; Figure 4A) and demonstrates RHD mRNA in these cell lines.
Kim concludes that TALENs can induce conversion of D positive cells into D negative cells by disrupting RHD, expanding the application of programmable nucleases into blood group conversion. The nuclease based blood group gene editing opens new avenues for the development of methods for converting blood groups in transfusion medicine (page 10, left column, paragraphs 4-5).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method disclosed by WO’620 by further including a genetic modification in the iPSC to reduce expression of RhD antigen, particularly when the iPSC were derived from RHD positive donors and when the patient is RHD negative and has been RHD sensitized during pregnancy with an RHD positive fetus or through an allogeneic RHD positive blood transfusion as taught by Kim. An ordinarily skilled artisan would have been motivated to further include a genetic modification to reduce RhD antigen expression as Kim teaches that the D antigen poses a danger for Rh D negative people and that Rh D negative persons can develop anti-Rh D antibodies upon first exposure (sensitized), which can induce immune responses against Rh D positive cells upon subsequent exposures. Additionally, Kim teaches that, when a sensitized patient is exposed again, the immune response can cause adverse effects, such as haemolysis. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’620 teaches that the iPSCs can be derived from non-pluripotent cells, such as CD34+ cord blood cells and fibroblasts, which Kim demonstrates can expresses RHD mRNA. Additionally, Kim teaches methods of genetically modifying cells to reduce Rh D antigen expression including the use of TALENs, which WO’620 also teaches can be used to modify nucleic acid sequences within the disclosed cells.
Regarding claims 210-212, as discussed above, the combination of WO’620 and Kim provide a reasonable expectation of the claimed outcomes. Specifically WO’620 teaches that the HIP cells, or cells differentiated therefrom, do not give rise to an immune response compared to a parental cell prior to immunoengineering. WO’620 also teaches that the cells do not elicit a T cell and/or B cell response and avoid innate immune response. Kim teaches that Rh D is the most immunogenic of the Rh antigens and that, when Rh D positive cells are given to an Rh D negative person anti-Rh D antibodies develop inducing an immune response against the Rh D positive cells.
Additionally, these outcomes are mechanistic results that would flow naturally from following the suggestions of the prior art and cannot be the basis for patentability when the differences would have otherwise been obvious. MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
Claims 190, 192, and 193 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/018620 A1 (Schrepfer, S., and T. Deuse) 23 Jan 2020 in view of Kim, Y.H., et al (2015) Rh D blood group conversion using transcription activator-like effector nucleases Nature Communications 6(7451); 1-13 as applied to claim 189 above, and in further view of Bolia, R. et al (2017) Rhesus alloimmunization occurs after Rh incompatible liver transplantation in children Transplantation 102(1); 1.
The combination of WO’620 and Kim teach the method of claim 189 as discussed in detail above.
As discussed above, Kim teaches that the Rh D antigen poses a danger for Rh D negative people. Because those who are Rh D negative do not have naturally occurring antibodies against the D antigen, adverse effects may not occur when the Rh D negative person is first exposed to Rh D positive cells; however, after such initial exposure, an Rh D negative patient can develop anti Rh D antibodies which can induce immune responses against Rh D positive cells and cause adverse effects.
The combination of WO’620 and Kim, however, does not disclose that the patient is RhD sensitized by receiving an allogeneic tissue or organ transplant as recited in claims 192-193.
Bolia teaches that, in theory, RhD negative recipients of RhD donor livers are at a risk of alloimmunization from the small amount of blood transplanted with a liver and subsequent development of anti-RhD antibodies. Patients who develop anti-RhD antibodies may be vulnerable to hemolytic transfusion reactions, which may lead to significant hemolysis and hemolytic disease (paragraph 1). Bolia teaches that some studies have shown a 15.7% risk of Rh alloimmunization in RhD negative adult liver transplant recipients of RhD incompatible blood products (paragraph 2). Bolia performed a review of medical records of patients who have undergone a Rh incompatible, that is a RhD positive donor and RhD negative recipient, liver transplants at the Royal Children Hospital in Melbourne (paragraph 3) and reports an approximate 5% incidence of RhD alloimmunization which is similar to studies concerning RhD incompatible kidney transplants (paragraphs 3).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method disclosed by WO’620 and Kim, by substituting the RhD sensitized patients, who were sensitized during pregnancy or with an allogeneic blood transplant, with patients who have been RhD sensitized from an allogenic organ/tissue transplant as taught by Bolia. It would have been obvious to treat this patient population with the hypoimmunogenic T cells taught by the combination of WO’620 and Kim and an ordinarily skilled artisan would have had a reasonable expectation of success because both the patients taught by the combination of WO’620 and Kim and Bolia are RhD negative and have been sensitized by exposure to RhD positive blood. Additionally, the cells taught by WO’620 and Kim have reduced expression of the RhD antigen and, therefore, would not cause an immune response in the patient who is RhD sensitized.
Claims 196 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/018620 A1 (Schrepfer, S., and T. Deuse) 23 Jan 2020 in view of Kim, Y.H., et al (2015) Rh D blood group conversion using transcription activator-like effector nucleases Nature Communications 6(7451); 1-13 as applied to claim 189 above, and in further view of Worel, N. (2016) ABO-mismatched allogeneic hematopoietic stem cell transplantation Transfus Med Hemother 43; 3-12.
The combination of WO’620 and Kim teach the method of claim 189 as discussed in detail above.
As discussed above, Kim teaches that the Rh D antigen poses a danger for Rh D negative people. Because those who are Rh D negative do not have naturally occurring antibodies against the D antigen, adverse effects may not occur when the Rh D negative person is first exposed to Rh D positive cells; however, after such initial exposure, an Rh D negative patient can develop anti Rh D antibodies which can induce immune responses against Rh D positive cells and cause adverse effects.
The combination of WO’620 and Kim, however, does not disclose that the patient is RhD sensitized by receiving an RhD+ cell therapy.
Worel teaches that allogenic hematopoietic stem cell transplantation is a curative option for a variety of malignant and non-malignant hematological and congenital diseases. Due to the fact that the human leukocyte antigen system is inherited independently of the blood group system, approximately 40-50% of all HSCTs are performed across the ABO blood group barrier. The expected immune hematological consequences after transplantation of an ABO-mismatched stem cell graft are immediate and delayed hemolytic complications due to the presence of isohemagglutinins or passenger lymphocyte syndrome (summary). Besides the ABO blood group system, Rhesus (Rh) antigens, especially the D antigen, are clinically the most significant factors for alloimmunization that usually occur after exposure of RhD negative individuals to RhD positive blood components (page 3, right column, paragraph 2). Worel teaches transfusion strategies from RhD positive donors to RhD negative recipients (page 10, table 3).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method disclosed by WO’620 and Kim, by substituting the RhD sensitized patients with patients who have been RhD sensitized from a RhD+ cell therapy, such as HSCT, as taught by Worel. It would have been obvious to treat this patient population with the hypoimmunogenic T cells taught by the combination of WO’620 and Kim and an ordinarily skilled artisan would have had a reasonable expectation of success because both the patients taught by the combination of WO’620 and Kim and Worel are RhD negative and are sensitized by exposure to RhD positive cells. Additionally, the modified cells taught by WO’620 and Kim have reduced expression of the RhD antigen and, therefore, would not cause an immune response in the patient who is RhD sensitized.
Claims 201-204 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/018620 A1 (Schrepfer, S., and T. Deuse) 23 Jan 2020 in view of Kim, Y.H., et al (2015) Rh D blood group conversion using transcription activator-like effector nucleases Nature Communications 6(7451); 1-13 as applied to claim 189 above, and in further view of WO 2016/183041 A2 (Meissner, T.B., et al) 17 Nov 2016.
The combination of WO’620 and Kim teach the method of claim 189 as discussed in detail above.
The combination of applied references does not disclose that the hypoimmunogenic T cells further comprised reduced expression of a TCR as recited in claim 201, that the cells do not express a TCR as recited in claim 202, or that the cells have reduced or no expression of TRAC and/or TRBC as recited in claims 203 and 204, respectively.
WO’041 teaches universal donor stem cells and their use and production. The universal donor stem cells disclosed are useful for overcoming the immune rejection in cell-based transplantation therapies. In certain embodiments, the cells do not express one or more MHC-I and MHC-II human leukocyte antigens, rendering the cells hypoimmunogenic (abstract). WO’041 also teaches that the cells also have increased expression of one or more tolerogenic factors to inhibit immune rejection including HLA-C, HLA-E, HLA-G, PD-L1, CTLA-4-Ig, CD47, C1-inhibitor, and IL-35 (page 3, lines 9-16).
WO’041 further teaches that genes encoding for T cell receptors can also be deleted by genome editing. Deletion of T cell receptor genes may occur to prevent autoimmune attack in T cell therapy. In some aspects, the gene encoding the T cell receptor is T cell receptor alpha locus (TRCA), which is also known as TRAC. In some aspects, the gene encoding the T cell receptor is a T cell receptor alpha locus (TCRB) (page 74, lines 3-14). WO’041 teaches that additional targets may be modified in universal donor cells to tailor them to be used as universal CAR T cells and exemplifies deletion of TRAC and TRBC to disrupt TCR expression. In the study, a dual guide RNA approach was used to introduce deletions into the TRAC and TRBC loci in HuES9 cells. WO’041 teaches the inventors additionally targeted TCRA in HuES9 B2M-/-CIITA-/- to create a triple knock out stem line for B2M-/-, CIITA-/-, and TCR-/-, which, upon differentiation into T cells, will be devoid of MHC-1 and -II and exhibit no TCR surface expression (page 84, lines 21-32). WO’041 also discloses that HuES9 is an iPSC line (page 77, lines 21-27).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of WO’620 and Kim by further reducing or knocking out expression of a TCR by genetically modifying the TRAC and/or TRBC as disclosed by WO’041. An ordinarily skilled artisan would have been motivated to further reduce or knockout a TCR in order to prevent autoimmune attack during T cell therapy. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’041 is also teaching hypoimmunogenic cells with the same modifications as WO’620, including MHC-I and MHC-II knockouts and increased expression of a tolerogenic factor, such as CD47. Additionally WO’041 also teaches the cells for use as CAR T cells and exemplifies the knockout of the TCR in an iPSC cell line.
Claims 189-191, 194-195, 197-200, and 205-212 are rejected under 35 U.S.C. 103 as being unpatentable over US 2020/0354673 A1 (Schrepfer, S. and T. Deuse) 12 Nov 2020; priority to 10 May 2019.
US’673 teaches hypoimmune pluripotent ABO blood type O Rhesus Factor negative (HIPO-) cells that evade rejection by the host allogeneic immune system and avoid blood antigen type rejection. The HIPO- cells are engineered to reduce or eliminate HLA-I and HLA-II expression, increase expression of an endogenous protein that reduces the susceptibility of the pluripotent cell to macrophage phagocytosis, and comprise a universal blood group O Rh- blood type. The universal blood type may be achieved by eliminating ABO blood group A and B antigens and Rh factor expression, or by starting with an O- cell line. These HIPO- cells evade host immune rejection because they have impaired antigen presentation capacity, protection from innate immune clearance, and lack blood group rection (page 2, [0018]).
US’673 teaches the generation of HIP cells in which two genetic changes are made to reduce or eliminate the protein activity of MHC I and II (HLA I and II when the cells are human). This can be done by altering genes encoding their component. In one embodiment, the coding region or regulatory sequences of the gene are disrupted using CRISPR or RNA technologies. The third modification includes increasing expression of a gene that regulates susceptibility to macrophage phagocytosis, such as CD47, which can be done using “knock in” of a gene using viral or transgene technologies (page 12, [0128]).
US’673 also teaches that the MHC I and MHC II reduction/elimination is achieved by the disruption of the B2M gene at each allele (B2M -/-) and the disruption of the CIITA gene at each allele (CIITA -/-) (page 17, [0207], [0211]).
US’673 teaches that the Rh blood group is the second most important blood group, after the ABO blood group system, and consists of 47 antigens, among which D, C, c, E, and e, are the most important. Rh(D) status of an individual is normally described with a positive or negative suffix after the ABO type. The terms “Rh factor” and “Rh positive” and “Rh negative” refer to the Rh(D) antigen only (page 2, [0011]). US’673 also teaches that the Rh- results from reducing or eliminating Rh protein expression through gene disruption (page 2, [0016]).
US’673 further teaches that the Rh- cells may be important for transplantation into previously sensitized subjects, and that such sensitization can occur through giving birth to a Rh+ baby or by receiving a Rh+ blood transfusion (page 21, [0255]; page 2, [0011]). US’673 also teaches methods of screening/stratifying the subject for administration of the cells, including subjects who are RH negative (pages 3-4, [0029]).
US’673 teaches cells derived from the PSCO-, iPSCO-, ESCO-, and/or HIPO-cells described, wherein the cells are selected from the group consisting of a chimeric antigen receptor (CAR) cell and, in a preferred embodiment, the CAR cell is a CAR T cell (page 3, [0023]).
US’673 further teaches a method of treating a patient with cancer by administering a composition comprising a therapeutically effective amount of any of the isolated O-CAR-T or HIPO-CAR-T cells (page 15, [0174]).
US’673 teaches that the CAR comprises an extracellular domain, a transmembrane domain, and an intracellular signaling domain. In some embodiments, the extracellular domain comprises an ScFv and binds to an antigen selected from the group consisting of CD19, CD20, CD22, CD38, CD123, CS1, CD171, BCMA, MUC16, ROR1, and WT1. US’673 also teaches CARs comprising two signaling domains (page 14, [0169]-[0170]).
While US’673 does not exemplify a method of treating a patient by administering the hypoimmunogenic T cells disclosed, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to arrive at the instantly claimed invention as US’673 teaches O Rh- hypoimmunogenic pluripotent cells, including iPSCs, with the claimed features and teaches that the cells can be differentiated into CAR T cells and administered in methods of treating cancer. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Regarding claims 210-212, as discussed above, WO’673 teaches that the HIPO- cells evade host immune rejection because they have impaired antigen presentation capacity, protection from innate immune clearance, and lack blood group rection providing a reasonable expectation of the claimed outcomes. Furthermore, these outcomes are mechanistic results that would flow naturally from following the suggestions of the prior art and cannot be the basis for patentability when the differences would have otherwise been obvious. MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
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.
US 12,221,622 B2
Claims 189-191, 194-195, 198-200, and 205-212 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-70 of U.S. Patent No. US 12,221,622 B2
in view of WO 2020/018620 A1 (Schrepfer, S., and T. Deuse) 23 Jan 2020 in view of Kim, Y.H., et al (2015) Rh D blood group conversion using transcription activator-like effector nucleases Nature Communications 6(7451); 1-13.
US’622 claims an isolated modified hypoimmunogenic human cell comprising a knockout of one or more genes encoding an ABO blood group antigen wherein the knock out renders the cell ABO blood group compatible with the recipient; a knockout of one or more genes encoding a Rh antigen, wherein the knock out renders the cell Rh-compatible with the recipient; or both. The cell also comprises a knockout of one or more MHC I (HLA I) genes which results in a reduced or eliminated surface expression of an HLA I complex compared to an unmodified wild type cell; and one or more CD47 transgenes that results in increased expression of CD47 compared to an unmodified cell.
US’622 further claims that one or more genes encoding an Rh antigen comprises a gene encoding an Rh D antigen.
US’622 claims that the cell further comprises a transgene which results in increased cell surface expression of PD-L1, HLA-G, CD200, FASLG, CLC21, MFGES, SERPIN 9, HLA-E, CTLA-4-Ig, CI-inhibitor, IL-35, or a combination thereof when compared to an unmodified or wild-type human cell.
US’622 further claims the one or more HLA-I associated genes comprise a beta-2 microglobulin (B2M) gene. The cell also further comprises a knock-out of one or more HLA-II genes, where the associated gene is CIITA.
US’622 further claims that the isolated modified cell is an O- induced pluripotent stem cell or an O-CAR cell, and that the O-CAR cell is a O-chimeric antigen receptor T cell.
US’622 differs from the instant claims in that US’622 does not claim a method of treating a disease, disorder, or condition comprising administering the T cells to a patient who is RhD sensitized.
The teachings of WO’620 and Kim are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the claims of US’622 to include a method of treating cancer comprising administration of the CAR T cells to a RhD sensitized patient based on the teachings of WO’620 and Kim. It would have been obvious to administer the CAR T cells to a patient for the treatment of cancer as WO’620 teaches hypoimmune pluripotent cells and hypoimmune CAR T cells for administration to patients for the treatment of cancer and Kim teaches that, when a Rh sensitized patient is exposed again, the immune response can cause adverse effects, such as haemolysis. An ordinarily skilled artisan would have had a reasonable expectation of success as US’622 and WO’620 both teach CAR T cells that do not express MHC class I or II molecules and overexpress tolerogenic factors, such as CD47, and Kim demonstrates the relevance of Rh- cells in the treatment of RhD sensitized patients.
Regarding claims 210-212, the teachings of WO’620 and Kim provide a reasonable expectation of the claimed outcomes. Specifically WO’620 teaches that the HIP cells, or cells differentiated therefrom, do not give rise to an immune response compared to a parental cell prior to immunoengineering. WO’620 also teaches that the cells do not elicit a T cell and/or B cell response and avoid innate immune response. Kim teaches that Rh D is the most immunogenic of the Rh antigens and that, when Rh D positive cells are given to an Rh D negative person anti-Rh D antibodies develop inducing an immune response against the Rh D positive cells.
Additionally, these outcomes are mechanistic results that would flow naturally from following the suggestions of the combination of US’622, WO’620, and Kim and cannot be the basis for patentability when the differences would have otherwise been obvious. MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
Claims 190, 192, and 193 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-70 of U.S. Patent No. US 12,221,622 B2 in view of WO 2020/018620 A1 (Schrepfer, S., and T. Deuse) 23 Jan 2020 in view of Kim, Y.H., et al (2015) Rh D blood group conversion using transcription activator-like effector nucleases Nature Communications 6(7451); 1-13 as discussed above, and in further view of Bolia, Rishi, et al (2017) Rhesus alloimmunization occurs after Rh incompatible liver transplantation in children Transplantation 102(1); 1.
The claims of US’622 modified by WO’620 and Kim teach the method of instant claim 189 as discussed in detail above.
The combination does not disclose that the patient is RhD sensitized by receiving an allogeneic tissue or organ transplant as recited in claims 192-193.
The teachings of Bolia are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of US’622, WO’620, and Kim, by substituting the RhD sensitized patients with patients who have been RhD sensitized from an allogenic organ/tissue transplant as taught by Bolia. It would have been obvious to treat this patient population with the hypoimmunogenic T cells taught by the combination of US’622, WO’620, and Kim and an ordinarily skilled artisan would have had a reasonable expectation of success because both the patients taught by the combination of US’622, WO’620, and Kim and Bolia are RhD negative and have been sensitized by exposure to RhD positive blood. Additionally, the cells taught by US’622, WO’620, and Kim have reduced/no expression of the RhD antigen and, therefore, would not cause an immune response in the patient who is RhD sensitized.
Claim 196 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-70 of U.S. Patent No. US 12,221,622 B2 in view of WO 2020/018620 A1 (Schrepfer, S., and T. Deuse) 23 Jan 2020 in view of Kim, Y.H., et al (2015) Rh D blood group conversion using transcription activator-like effector nucleases Nature Communications 6(7451); 1-13 as discussed above, and in further view of Worel, N. (2016) ABO-mismatched allogeneic hematopoietic stem cell transplantation Transfus Med Hemother 43; 3-12.
The claims of US’622 modified by WO’620 and Kim teach the method of instant claim 189 as discussed in detail above.
The combination does not disclose that the patient is RhD sensitized by receiving an RhD+ cell therapy.
The teachings of Worel are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by US’622 modified by WO’620 and Kim, by substituting the RhD sensitized patients with patients who have been RhD sensitized from a RhD+ cell therapy, such as HSCT, as taught by Worel. It would have been obvious to treat this patient population with the hypoimmunogenic T cells taught by the combination of US’622, WO’620 and Kim and an ordinarily skilled artisan would have had a reasonable expectation of success because both the patients taught by the combination of US’622, WO’620 and Kim and Worel are RhD negative and are sensitized by exposure to RhD positive blood. Additionally, the cells taught by US’622, WO’620 and Kim have reduced expression of the RhD antigen and, therefore, would not cause an immune response in the patient who is RhD sensitized.
Claims 201-204 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-70 of U.S. Patent No. US 12,221,622 B2 in view of WO 2020/018620 A1 (Schrepfer, S., and T. Deuse) 23 Jan 2020 in view of Kim, Y.H., et al (2015) Rh D blood group conversion using transcription activator-like effector nucleases Nature Communications 6(7451); 1-13 as discussed above, and in further view of WO 2016/183041 A2 (Meissner, T.B., et al) 17 Nov 2016.
The claims of US’622 modified by WO’620 and Kim teach the method of instant claim 189 as discussed in detail above.
The combination does not disclose that the hypoimmunogenic T cells further comprised reduced expression of a TCR as recited in claim 201, that the cells do not express a TCR as recited in claim 202, or that the cells have reduced or no expression of TRAC and/or TRBC as recited in claims 203 and 204, respectively.
The teachings of WO’041 are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by US’622 modified by WO’620 and Kim by further reducing or knocking out expression of a TCR by genetically modifying the TRAC and/or TRBC as disclosed by WO’041. An ordinarily skilled artisan would have been motivated to further reduce or knockout a TCR in order to prevent autoimmune attack during T cell therapy. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’041 is also teaching hypoimmunogenic cells with the same modifications as US’622 and WO’620, including MHC-I and MHC-II knockouts and increased expression of a tolerogenic factor, such as CD47. Additionally WO’041 also teaches the cells for use as CAR T cells and exemplifies the knockout of the TCR in an iPSC cell line.
17/260,222
Claims 189-191, 194-195, 198-200, and 205-212 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-15, 32-37, 53, and 59-62 of copending Application No. 17/260,222 in view of WO 2020/018620 A1 (Schrepfer, S., and T. Deuse) 23 Jan 2020 in view of Kim, Y.H., et al (2015) Rh D blood group conversion using transcription activator-like effector nucleases Nature Communications 6(7451); 1-13.
App’222 claims a population of hypoimmunogenic T cells comprising a nucleic acid encoding a CAR, wherein endogenous B2M gene activity and endogenous CIITA gene activity is eliminated; and CD47 expression is increased compared to a wild type. App’222 further claims that the population of T cells comprises at least about 6% CD8+CD45RA+CCR7- T cells and that the population of T cell sis produced by in vitro differentiation of pluripotent stem cells.
App’222 further claims that the Car comprises an extracellular domain, a hinge region, a transmembrane domain, and/or an intracellular signaling domain. App’222 claims that the extracellular domain binds CD19, CD20, CD22, CD38, CD123, CD171, CSI, BCMA, MUC16, ROR1, or WTI, or any combination thereof and that the extracellular domain comprises an scFv, a synthetic antibody, a human antibody, a humanized antibody, a non-human antibody, a nanobody, a F(ab’)2, a Fab’, a Fab, or an Fv.
App’222 further claims that the elimination of B2M and CIITA gene activity results from one or more genetic alterations that reduce expression of B2M and CIITA.
App’222 further claims a method of administering the population of hypoimmunogenic T cells to a subject, including for the treatment of cancer.
The claims of App’222 differ from the instantly claimed invention in that App’222 does not claim one or more genetic modifications to reduce expression of RhD antigen relative to reference cells of the same cell type or that the patient is RhD sensitized.
The teachings of WO’620 and Kim are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method disclosed by App’222 by further including a genetic modification in the iPSC to reduce expression of RhD antigen, particularly when the iPSC were derived from RHD positive donors and when the patient is RHD negative and has been RHD sensitized during pregnancy with an RHD positive fetus or through a RHD positive blood transfusion as taught by Kim. An ordinarily skilled artisan would have been motivated to further include a genetic modification to reduce RhD antigen expression as Kim teaches that the D antigen poses a danger for Rh D negative people and that Rh D negative persons can develop anti-Rh D antibodies upon first exposure (sensitized), which can induce immune responses against Rh D positive cells upon subsequent exposures. Additionally, Kim teaches that, when a sensitized patient is exposed again, the immune response can cause adverse effects, such as haemolysis. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’620 teaches that iPSCs are made from non-pluripotent cells, such as CD34+ cord blood cells and fibroblasts, which Kim demonstrates expresses RHD. Additionally, Kim teaches methods of genetically modifying cells to reduce RH D antigen expression including the use of TALENs, which WO’620 also teaches can be used to modify nucleic acid sequences within the disclosed cells.
Regarding claims 210-212, the combination of WO’620 and Kim provide a reasonable expectation of the claimed outcomes. Specifically WO’620 teaches that the HIP cells, or cells differentiated therefrom, do not give rise to an immune response compared to a parental cell prior to immunoengineering. WO’620 also teaches that the cells do not elicit a T cell and/or B cell response and avoid innate immune response. Kim teaches that Rh D is the most immunogenic of the Rh antigens and that, when Rh D positive cells are given to an Rh D negative person anti-Rh D antibodies develop inducing an immune response against the Rh D positive cells.
Additionally, these outcomes are mechanistic results that would flow naturally from following the suggestions of the prior art and cannot be the basis for patentability when the differences would have otherwise been obvious. MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
Claims 190, 192, and 193 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-15, 32-37, 53, and 59-62 of copending Application No. 17/260,222 in view of WO 2020/018620 A1 (Schrepfer, S., and T. Deuse) 23 Jan 2020 in view of Kim, Y.H., et al (2015) Rh D blood group conversion using transcription activator-like effector nucleases Nature Communications 6(7451); 1-13 as discussed above, and in further view of Bolia, Rishi, et al (2017) Rhesus alloimmunization occurs after Rh incompatible liver transplantation in children Transplantation 102(1); 1.
The claims of App’222 modified by WO’620 and Kim teach the method of instant claim 189 as discussed in detail above.
The combination does not disclose that the patient is RhD sensitized by receiving an allogeneic tissue or organ transplant as recited in claims 192-193.
The teachings of Bolia are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of App’222, WO’620, and Kim, by substituting the RhD sensitized patients with patients who have been RhD sensitized from an allogenic organ/tissue transplant as taught by Bolia. It would have been obvious to treat this patient population with the hypoimmunogenic T cells taught by the combination of App’222, WO’620, and Kim and an ordinarily skilled artisan would have had a reasonable expectation of success because both the patients taught by the combination of App’222, WO’620, and Kim and Bolia are RhD negative and have been sensitized by exposure to RhD positive blood. Additionally, the cells taught by App’222, WO’620, and Kim have reduced/no expression of the RhD antigen and, therefore, would not cause an immune response in the patient who is RhD sensitized.
Claim 196 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-15, 32-37, 53, and 59-62 of copending Application No. 17/260,222 in view of WO 2020/018620 A1 (Schrepfer, S., and T. Deuse) 23 Jan 2020 in view of Kim, Y.H., et al (2015) Rh D blood group conversion using transcription activator-like effector nucleases Nature Communications 6(7451); 1-13 as discussed above, and in further view of Worel, N. (2016) ABO-mismatched allogeneic hematopoietic stem cell transplantation Transfus Med Hemother 43; 3-12.
The claims of App’222 modified by WO’620 and Kim teach the method of instant claim 189 as discussed in detail above.
The combination does not disclose that the patient is RhD sensitized by receiving an RhD+ cell therapy.
The teachings of Worel are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by App’222 modified by WO’620 and Kim, by substituting the RhD sensitized patients with patients who have been RhD sensitized from a RhD+ cell therapy, such as HSCT, as taught by Worel. It would have been obvious to treat this patient population with the hypoimmunogenic T cells taught by the combination of App’222, WO’620 and Kim and an ordinarily skilled artisan would have had a reasonable expectation of success because both the patients taught by the combination of App’222, WO’620 and Kim and Worel are RhD negative and are sensitized by exposure to RhD positive blood. Additionally, the cells taught by App’222, WO’620 and Kim have reduced expression of the RhD antigen and, therefore, would not cause an immune response in the patient who is RhD sensitized.
Claims 201-204 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-15, 32-37, 53, and 59-62 of copending Application No. 17/260,222 in view of WO 2020/018620 A1 (Schrepfer, S., and T. Deuse) 23 Jan 2020 and Kim, Y.H., et al (2015) Rh D blood group conversion using transcription activator-like effector nucleases Nature Communications 6(7451); 1-13 as discussed above, and in further view of WO 2016/183041 A2 (Meissner, T.B., et al) 17 Nov 2016.
The claims of App’222 modified by WO’620 and Kim teach the method of instant claim 189 as discussed in detail above.
The combination does not disclose that the hypoimmunogenic T cells further comprised reduced expression of a TCR as recited in claim 201, that the cells do not express a TCR as recited in claim 202, or that the cells have reduced or no expression of TRAC and/or TRBC as recited in claims 203 and 204, respectively.
The teachings of WO’041 are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by App’222 modified by WO’620 and Kim by further reducing or knocking out expression of a TCR by genetically modifying the TRAC and/or TRBC as disclosed by WO’041. An ordinarily skilled artisan would have been motivated to further reduce or knockout a TCR in order to prevent autoimmune attack during T cell therapy. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’041 is also teaching hypoimmunogenic cells with the same modifications as App’222 and WO’620, including MHC-I and MHC-II knockouts and increased expression of a tolerogenic factor, such as CD47. Additionally WO’041 also teaches the cells for use as CAR T cells and exemplifies the knockout of the TCR in an iPSC cell line.
This is a provisional nonstatutory double patenting rejection.
17/607,841
Claims 189-191, 194-195, 198-200, and 205-212 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 8, 17, 35, 40, 51, 61, 63, 66-67, 69, 80, 83, 106, 109, 120, and 124-125 of copending Application No. 17/607,841 in view of WO 2020/018620 A1 (Schrepfer, S., and T. Deuse) 23 Jan 2020 and Kim, Y.H., et al (2015) Rh D blood group conversion using transcription activator-like effector nucleases Nature Communications 6(7451); 1-13.
App’841 claims a modified pluripotent cell, wherein the cell is ABO blood group type O and Rh negative and has reduced or eliminated Rh protein antigen expression or reduced or eliminated antigenicity of one or more ABO and/or Rh antigens; and wherein the modified cell is a hypoimmunogenic pluripotent HIP cell comprising an endogenous MHC I (HLA-I) ad MHC II (HLA-II) function that is reduced when compared to an unmodified cell and an increase in CD47 function that reduces susceptibility to NK cell killing.
App’841 further claims that the HLA-I function is reduced by a reduction in B2M protein or wherein a gene encoding B2M protein is knocked out and HLA-II function is reduced by a reduction in expression of CIITA protein or wherein a gene encoding CIITA protein is knocked out.
App’841 further claims a cell derived from the modified pluripotent cell including an O-CAR and O-CAR T cell.
App’841 differs from the instantly claimed invention in that App’841 does not claim a method of treating a disease, disorder, or condition comprising administering the T cells to a patient who is RhD sensitized.
The teachings of WO’620 and Kim are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the claims of App’841 to include a method of treating cancer comprising administration of the CAR T cells to a RhD sensitized patient based on the teachings of WO’620 and Kim. It would have been obvious to administer the CAR T cells to a patient for the treatment of cancer as WO’620 teaches hypoimmune pluripotent cells and hypoimmune CAR T cells for administration to patients for the treatment of cancer and Kim teaches that, when a Rh sensitized patient is exposed again, the immune response can cause adverse effects, such as haemolysis. An ordinarily skilled artisan would have had a reasonable expectation of success as App’841 and WO’620 both teach CAR T cells that do not express MHC class I or II molecules and overexpress tolerogenic factors, such as CD47, and Kim demonstrates the relevance of Rh- cells in the treatment of RhD sensitized patients.
Regarding claims 210-212, the teachings of WO’620 and Kim provide a reasonable expectation of the claimed outcomes. Specifically WO’620 teaches that the HIP cells, or cells differentiated therefrom, do not give rise to an immune response compared to a parental cell prior to immunoengineering. WO’620 also teaches that the cells do not elicit a T cell and/or B cell response and avoid innate immune response. Kim teaches that Rh D is the most immunogenic of the Rh antigens and that, when Rh D positive cells are given to an Rh D negative person anti-Rh D antibodies develop inducing an immune response against the Rh D positive cells.
Additionally, these outcomes are mechanistic results that would flow naturally from following the suggestions of the combination of App’841, WO’620, and Kim and cannot be the basis for patentability when the differences would have otherwise been obvious. MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
Claims 190, 192, and 193 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 8, 17, 35, 40, 51, 61, 63, 66-67, 69, 80, 83, 106, 109, 120, and 124-125 of copending Application No. 17/607,841 in view of WO 2020/018620 A1 (Schrepfer, S., and T. Deuse) 23 Jan 2020 and Kim, Y.H., et al (2015) Rh D blood group conversion using transcription activator-like effector nucleases Nature Communications 6(7451); 1-13 as discussed above, and in further view of Bolia, Rishi, et al (2017) Rhesus alloimmunization occurs after Rh incompatible liver transplantation in children Transplantation 102(1); 1.
The claims of App’841 modified by WO’620 and Kim teach the method of instant claim 189 as discussed in detail above.
The combination does not disclose that the patient is RhD sensitized by receiving an allogeneic tissue or organ transplant as recited in claims 192-193.
The teachings of Bolia are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of App’841, WO’620, and Kim, by substituting the RhD sensitized patients with patients who have been RhD sensitized from an allogenic organ/tissue transplant as taught by Bolia. It would have been obvious to treat this patient population with the hypoimmunogenic T cells taught by the combination of App’841, WO’620, and Kim and an ordinarily skilled artisan would have had a reasonable expectation of success because both the patients taught by the combination of App’841, WO’620, and Kim and Bolia are RhD negative and have been sensitized by exposure to RhD positive blood. Additionally, the cells taught by App’841, WO’620, and Kim have reduced/no expression of the RhD antigen and, therefore, would not cause an immune response in the patient who is RhD sensitized.
Claim 196 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 8, 17, 35, 40, 51, 61, 63, 66-67, 69, 80, 83, 106, 109, 120, and 124-125 of copending Application No. 17/607,841 in view of WO 2020/018620 A1 (Schrepfer, S., and T. Deuse) 23 Jan 2020 in view of Kim, Y.H., et al (2015) Rh D blood group conversion using transcription activator-like effector nucleases Nature Communications 6(7451); 1-13 as discussed above, and in further view of Worel, N. (2016) ABO-mismatched allogeneic hematopoietic stem cell transplantation Transfus Med Hemother 43; 3-12.
The claims of App’841 modified by WO’620 and Kim teach the method of instant claim 189 as discussed in detail above.
The combination does not disclose that the patient is RhD sensitized by receiving an RhD+ cell therapy.
The teachings of Worel are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by App’841 modified by WO’620 and Kim, by substituting the RhD sensitized patients with patients who have been RhD sensitized from a RhD+ cell therapy, such as HSCT, as taught by Worel. It would have been obvious to treat this patient population with the hypoimmunogenic T cells taught by the combination of App’841, WO’620 and Kim and an ordinarily skilled artisan would have had a reasonable expectation of success because both the patients taught by the combination of App’841, WO’620 and Kim and Worel are RhD negative and are sensitized by exposure to RhD positive blood. Additionally, the cells taught by App’841, WO’620 and Kim have reduced expression of the RhD antigen and, therefore, would not cause an immune response in the patient who is RhD sensitized.
Claims 201-204 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 8, 17, 35, 40, 51, 61, 63, 66-67, 69, 80, 83, 106, 109, 120, and 124-125 of copending Application No. 17/607,841 in view of WO 2020/018620 A1 (Schrepfer, S., and T. Deuse) 23 Jan 2020 in view of Kim, Y.H., et al (2015) Rh D blood group conversion using transcription activator-like effector nucleases Nature Communications 6(7451); 1-13 as discussed above, and in further view of WO 2016/183041 A2 (Meissner, T.B., et al) 17 Nov 2016.
The claims of App’841 modified by WO’620 and Kim teach the method of instant claim 189 as discussed in detail above.
The combination does not disclose that the hypoimmunogenic T cells further comprised reduced expression of a TCR as recited in claim 201, that the cells do not express a TCR as recited in claim 202, or that the cells have reduced or no expression of TRAC and/or TRBC as recited in claims 203 and 204, respectively.
The teachings of WO’041 are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by App’841 modified by WO’620 and Kim by further reducing or knocking out expression of a TCR by genetically modifying the TRAC and/or TRBC as disclosed by WO’041. An ordinarily skilled artisan would have been motivated to further reduce or knockout a TCR in order to prevent autoimmune attack during T cell therapy. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’041 is also teaching hypoimmunogenic cells with the same modifications as App’841 and WO’620, including MHC-I and MHC-II knockouts and increased expression of a tolerogenic factor, such as CD47. Additionally WO’041 also teaches the cells for use as CAR T cells and exemplifies the knockout of the TCR in an iPSC cell line.
This is a provisional nonstatutory double patenting rejection.
18/021,036
Claims 189-191, 194-195, 198-200, and 205-212 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 312, 314-317, 319-330, and 332-340 of copending Application No. 18/021,036 in view of WO 2020/018620 A1 (Schrepfer, S., and T. Deuse) 23 Jan 2020 in view of Kim, Y.H., et al (2015) Rh D blood group conversion using transcription activator-like effector nucleases Nature Communications 6(7451); 1-13.
App’036 claims a method of treating a disease, disorder, or condition in a patient comprising administering a population of hypoimmunogenic cells, wherein the population of cells have been modified to: express CD47 and include one or more genetic modifications that reduce the cell surface expression of MHC I molecules, MHC class II molecules, or both, wherein the reduced cell surface expression is relative to a reference cell of the same cell type that does not comprise the genomic modifications, wherein the patient exhibits memory B and/or T cells reactive against one or more alloantigens or one or more autologous antigens.
App’036 further claims that the one or more modifications that reduce expression of MHC I or MHC II molecules include one or more modifications that reduce expression of B2M, CIITA, or both.
App’036 further claims that the cells have been further modified to express one or more molecules chosen from DUX4, CD24, Cd27, CD46, CD55, CD59, CD200, HLA-C, HLA-E, HLA-E heavy chain, HLA-G, PD-L1, IDO1, CTLA4-Ig, C1-inhibitor, IL-10, IL-35, IL-39: Fas1, CCL21, CCL22, MfgeS, Serpinb9, CD16 Fc receptor, IL15-RF, CD16, CD52, H2-M3, CD35, or any combination thereof.
App’036 further claims that the memory B and/or T cells arose from a previous transplant, a previous pregnancy, and/or a previous treatment of the patient for a condition or disease.
App’036 further claims that the hypoimmunogenic cells can be T cells, including CAR T cells, or primary T cells.
App’036 claims that the patient had previously exhibited alloimmunization in pregnancy.
App’036 claims that the hypoimmunogenic cells were differentiated from stem cells, including IPSCs.
App’036 further claims that the cells comprise a CAR and that the CAR comprises a first, second, third, or fourth generation CAR. Where the antigen binding domain targets an antigen characteristic of a neoplastic cell, a T cell, an autoimmune or inflammatory disorder, a senescent cell, an infectious disease, or a cell surface antigen of a cell; where the antigen binding domain is an scFv or a Fab, and the domain binds CD19, CD20, CD22, BCMA, or a combination thereof. App’036 further claims that the patient does not exhibit an immune response after administration of the cells including one or more of a systemic TH1 activation, an immune activation of PBMCs, a donor specific IgG antibodies, IgM and IgG antibody production, or a cytotoxic T cell killing of the cells.
The claims of App’036 differ from the instantly claimed invention in that App’036 does not explicitly claim one or more genetic modifications to reduce expression of RhD antigen relative to reference cells of the same cell type or that the patient is RhD sensitized.
The teachings of WO’620 and Kim are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method disclosed by App’036 by further including a genetic modification in the iPSC to reduce expression of RhD antigen, particularly when the iPSC were derived from RHD positive donors and when the patient is RHD negative and has been RHD sensitized during pregnancy with an RHD positive fetus or through a RHD positive blood transfusion as taught by Kim. An ordinarily skilled artisan would have been motivated to further include a genetic modification to reduce RhD antigen expression as Kim teaches that the D antigen poses a danger for Rh D negative people and that Rh D negative persons can develop anti-Rh D antibodies upon first exposure (sensitized), which can induce immune responses against Rh D positive cells upon subsequent exposures. Additionally, Kim teaches that, when a sensitized patient is exposed again, the immune response can cause adverse effects, such as haemolysis. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’620 teaches that iPSCs are made from non-pluripotent cells, such as CD34+ cord blood cells and fibroblasts, which Kim demonstrates expresses RHD. Additionally, Kim teaches methods of genetically modifying cells to reduce RH D antigen expression including the use of TALENs, which WO’620 also teaches can be used to modify nucleic acid sequences within the disclosed cells.
Regarding claims 210-212, as discussed above, App’036 recites limitations recited in instant claims 210 and 212. WO’620 also provides a reasonable expectation that the cells would avoid an innate immune response and T cell/B cell responses
Additionally, these outcomes are mechanistic results that would flow naturally from following the suggestions of the prior art and cannot be the basis for patentability when the differences would have otherwise been obvious. MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
Claims 190, 192, and 193 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 312, 314-317, 319-330, and 332-340 of copending Application No. 18/021,036 in view of WO 2020/018620 A1 (Schrepfer, S., and T. Deuse) 23 Jan 2020 in view of Kim, Y.H., et al (2015) Rh D blood group conversion using transcription activator-like effector nucleases Nature Communications 6(7451); 1-13 as discussed above, and in further view of Bolia, Rishi, et al (2017) Rhesus alloimmunization occurs after Rh incompatible liver transplantation in children Transplantation 102(1); 1.
The claims of App’036 modified by WO’620 and Kim teach the method of instant claim 189 as discussed in detail above.
The combination does not disclose that the patient is RhD sensitized by receiving an allogeneic tissue or organ transplant as recited in claims 192-193.
The teachings of Bolia are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of App’036, WO’620, and Kim, by substituting the RhD sensitized patients with patients who have been RhD sensitized from an allogenic organ/tissue transplant as taught by Bolia. It would have been obvious to treat this patient population with the hypoimmunogenic T cells taught by the combination of App’036, WO’620, and Kim and an ordinarily skilled artisan would have had a reasonable expectation of success because both the patients taught by the combination of App’036, WO’620, and Kim and Bolia are RhD negative and have been sensitized by exposure to RhD positive blood. Additionally, the cells taught by App’036, WO’620, and Kim have reduced/no expression of the RhD antigen and, therefore, would not cause an immune response in the patient who is RhD sensitized.
Claim 196 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 312, 314-317, 319-330, and 332-340 of copending Application No. 18/021,036 in view of WO 2020/018620 A1 (Schrepfer, S., and T. Deuse) 23 Jan 2020 in view of Kim, Y.H., et al (2015) Rh D blood group conversion using transcription activator-like effector nucleases Nature Communications 6(7451); 1-13 as discussed above, and in further view of Worel, N. (2016) ABO-mismatched allogeneic hematopoietic stem cell transplantation Transfus Med Hemother 43; 3-12.
The claims of App’036 modified by WO’620 and Kim teach the method of instant claim 189 as discussed in detail above.
The combination does not disclose that the patient is RhD sensitized by receiving an RhD+ cell therapy.
The teachings of Worel are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by App’036 modified by WO’620 and Kim, by substituting the RhD sensitized patients with patients who have been RhD sensitized from a RhD+ cell therapy, such as HSCT, as taught by Worel. It would have been obvious to treat this patient population with the hypoimmunogenic T cells taught by the combination of App’036, WO’620 and Kim and an ordinarily skilled artisan would have had a reasonable expectation of success because both the patients taught by the combination of App’036, WO’620 and Kim and Worel are RhD negative and are sensitized by exposure to RhD positive blood. Additionally, the cells taught by App’036, WO’620 and Kim have reduced expression of the RhD antigen and, therefore, would not cause an immune response in the patient who is RhD sensitized.
Claims 201-204 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 312, 314-317, 319-330, and 332-340 of copending Application No. 18/021,036 in view of WO 2020/018620 A1 (Schrepfer, S., and T. Deuse) 23 Jan 2020 and Kim, Y.H., et al (2015) Rh D blood group conversion using transcription activator-like effector nucleases Nature Communications 6(7451); 1-13 as discussed above, and in further view of WO 2016/183041 A2 (Meissner, T.B., et al) 17 Nov 2016.
The claims of App’036 modified by WO’620 and Kim teach the method of instant claim 189 as discussed in detail above.
The combination does not disclose that the hypoimmunogenic T cells further comprised reduced expression of a TCR as recited in claim 201, that the cells do not express a TCR as recited in claim 202, or that the cells have reduced or no expression of TRAC and/or TRBC as recited in claims 203 and 204, respectively.
The teachings of WO’041 are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by App’036 modified by WO’620 and Kim by further reducing or knocking out expression of a TCR by genetically modifying the TRAC and/or TRBC as disclosed by WO’041. An ordinarily skilled artisan would have been motivated to further reduce or knockout a TCR in order to prevent autoimmune attack during T cell therapy. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’041 is also teaching hypoimmunogenic cells with the same modifications as App’036 and WO’620, including MHC-I and MHC-II knockouts and increased expression of a tolerogenic factor, such as CD47. Additionally WO’041 also teaches the cells for use as CAR T cells and exemplifies the knockout of the TCR in an iPSC cell line.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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