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 .
DETAILED ACTION
Status of Claims
Applicant's preliminary amendment of the instant application, which was originally submitted on 08/16/2023 and later amended on 01/16/2024, is acknowledged by the Examiner. The cancellation of claims 2, 8, 9, 11, 15, 18, 19, 21, 25, 37, 39 – 41, 43, 48, 50, 55, 56, and 62 pursuant to the amendment on 01/16/2024 is acknowledged. Claims 1, 3 – 7, 10, 12 – 14, 16, 17, 20, 22 – 24, 26 – 36, 38, 42, 44 – 47, 49, 51 – 54, 57 – 61, and 63 were previously examined and restricted in the Office Action mailed on 01/08/2026.
Election/Restrictions
Applicant’s election without traverse of a method of making engineered immune cells to prevent or inhibit human herpes virus 6 (HHV-6) replication, transcription activation, infection or replication or infection after reactivation, i.e., Group I, in the reply filed on 02/10/2026 is acknowledged. Applicant’s election of the chimeric antigen receptor (CAR) as the immune cell receptor; interferon (IFN) as the antiviral agent; T cells as the type of immune cell; RNA as the type of genetic material; and lentivirus as the virus in the reply filed on 02/10/2026 is also acknowledged.
Claims 28 – 36 and 38 and claims 12, 13, 51, and 52 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species, respectively, there being no allowable generic or linking claim.
The species election of the vector is hereby withdrawn to expedite prosecution, but all other restriction/election requirements stand.
Election was made without traverse in the reply filed on 02/10/2026. Claims 1, 3 – 7, 10, 14, 16, 17, 20, 22 – 24, 26, 27, 42, 44 – 47, 49, 53, 54, 57 – 61, and 63 are pending and under review.
Priority
The instant application claims priority to U.S. Provisional Application No. 63/398364 filed on 08/16/2022 and U.S. Provisional Application No. 63/510025 filed on 06/23/2023. Priority is granted to the provisional application filed 08/16/2022 for current claims 1, 3 – 7, 10, 14, 16, 17, 20, 22 – 24, 26, 27, 42, 44 – 47, 49, 53, 54, 57 – 61, and 63 of the instant application. Thus, the U.S. effective filing date of the instant application is 08/16/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/23/2024 has been considered by the Examiner. Notably, the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Thus, unless the references have been cited by the Examiner on form PTO-892, they have not been considered.
Specification
The use of the terms nCounter® on pages 7, 56, and 57; CyroStor® on page 14; Zybodies® on pages 18 and 19; Probodies® on pages 18 and 19; SMIPs™ on pages 18 and 19; TandAb® pages 18 and 19; Anticalins® on page 18 and 19; Nanobodies® on page 18 and 19; BiTE® on page 18 and 19; DARPINs® on page 18 and 19; Avimers® on page 18 and 19; Adnectins® on page 18 and 19; Affilins® on page 18 and 19; Trans-bodies® on page 18 and 19; Affibodies® on page 18 and 19; TrimerX® on page 18 and 19; Fynomers® on page 18 and 19, Centyrins® on page 18 and 19; KALBITOR® on page 18 and 19; TALEN® on page 29; FICOLL™ on page 34; PERCOLL™ on page 34; TransAct™ on page 36; Normosol™ on pages 37 and 41; Plasma-Lyte™ on pages 37 and 41; CYTOTAX™ on page 48; PSK® on page 48; TAXOL™ on page 48; TAXOTERE® on page 48; Targretin™ on page 49; Panretin™ on page 49; ONTAK™ on page 49; Cytoxan® on page 49; Oncovin® onpage 49; Opdivo® on page 49; Keytruda® on page 49; Tcentriq® on page 48; Imbruvica® on page 49; Arzerra® on page 49; Rituxan® on page 49; Avastin® on page 49; Herceptin® on page 49; KADCYLA® on page 50; Gleevec® on page 50; Erbitux® on page 50; Vectibix® on page 50; ENBREL® on page 50; HUMIRA® on page 50; REMICADE® on page 50; TaqMan™ on page 62;and possibly others in the specification, which are trade names or a marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, ℠, or ® following the terms. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Applicant is required to properly annotate all trade names and/or marks that are present in the specification.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which Applicant may become aware in the specification.
Drawings
The drawings are objected to because Figure 5A has a text box that recites "[I]nfection a...". It is unclear what is meant by this recitation. Additionally, Figures 6A, 6B, 7A, and 7B are missing y-axis labels.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the Examiner, the Applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 1, 14, 16, 23, 42, 53, and 60 are objected to because of the following informalities:
In claim 1, line 1 and claim 42, line 4, the acronym “HHV-6” is recited, but not defined in the claim. An acronym should be defined the first time it appears in an independent claim or in the group of claims under an independent claim. For the purposes of examination, “HHV-6” is interpreted to mean “Human herpesvirus 6”, as defined in paragraph 0004 on page 1 of the instant specification;
There is a typographical error in claim 1, line 8. There is a missing comma after “optionally”, wherein the phrase should read “optionally, wherein”;
There is a typographical error in line 2 of claims 14 and 53. There is a missing comma after “IPSCs”, wherein the phrase should read “IPSCs, or NK cells”;
In claims 14 and 53, line 2, the acronym “PBMCs” is recited, but not defined in the claim. An acronym should be defined the first time it appears in an independent claim or in the group of claims under an independent claim. For the purposes of examination, “PBMCs” is interpreted to mean “peripheral blood mononuclear cells”, as discussed in paragraph 0059 on page 16 of the instant specification;
In claims 14 and 53, line 2, the acronym “iPSCs” is recited, but not defined in the claim. An acronym should be defined the first time it appears in an independent claim or in the group of claims under an independent claim. For the purposes of examination, “iPSCs” is interpreted to mean “induced pluripotent stem cells”, as discussed in paragraph 0131 on page 35 of the instant specification;
In claims 14 and 53, line 2, the acronym “NK” is recited, but not defined in the claim. An acronym should be defined the first time it appears in an independent claim or in the group of claims under an independent claim. For the purposes of examination, “NK” is interpreted to mean “Natural killer”, as discussed in paragraph 0088 on page 24 of the instant specification;
In claim 16, line 2, the acronym “Tcm” is recited, but not defined in the claim. An acronym should be defined the first time it appears in an independent claim or in the group of claims under an independent claim. For the purposes of examination, “Tcm” is interpreted to mean “central memory T cells”, as discussed in paragraph 0050 on page 14 of the instant specification. Additionally, the proper abbreviation is to have CM capitalized and subscripted to read “TCM”;
In claim 16, line 2, the acronym “Tscm” is recited, but not defined in the claim. An acronym should be defined the first time it appears in an independent claim or in the group of claims under an independent claim. For the purposes of examination, “Tscm” is interpreted to mean “stem cell memory T cells”, as discussed in paragraph 0050 on page 14 of the instant specification. Additionally, the proper abbreviation is to have SCM capitalized and subscripted to read “TSCM”;
In claims 23 and 60, line 2, the acronym “TCRα” is recited, but not defined in the claim. An acronym should be defined the first time it appears in an independent claim or in the group of claims under an independent claim. For the purposes of examination, “TCRα” is interpreted to mean “T-cell receptor alpha chain”, as discussed in paragraph 0015 on page 6 of the instant specification.
Recommended amendments are underlined. Appropriate correction is required.
Claim Rejections - 35 USC § 112
35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION. — The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the Applicant regards as his invention.
Claims 3 – 6, 10, 44 – 47, 49, and 63 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.
Claims 3 – 6 and 44 – 47 are vague and unclear, which renders the claim indefinite. The claims recite different timeframes, i.e., days, that the antiviral agent can be added to the culture medium. It is not clear if this is how or if the antiviral agent is added to the media once during the entire timeframe? The presence of multiple very different interpretations of the same claim language renders the claim indefinite. For this examination, in view of example 6 (paragraphs 0200 – 0202) on pages 60 and 61 of the instant specification, it will be inferred that the antiviral agent, i.e., IFN, is added to the culture medium once during the entire timeframe. However, an appropriate amendment is required.
The term “about” in claims 6, 10, 47, and 49 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification does not define the degree of variability that is encompassed by “about”. This term is subjective and multiple practitioners could have varying opinions on what constitutes “particularly” any particular value. Thus, the claims that recite “particularly” are rendered indefinite. It is suggested that every iteration of the term be removed in its current usage.
Claim 63 recites the limitation "the IFN" in line 1 of the claim. There is insufficient antecedent basis for this limitation in the claim. There is no recitation of the IFN in claim 42, upon which claim 63 depends, and so it is not clear the role it plays in the claimed method of claim 63. For this examination, it will be inferred that the antiviral agent is IFN, as described in claim 49. However, an appropriate amendment is required.
It is noted that any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to this Office Action. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejection(s) and art may be applied in a subsequent Office Action.
Improper Markush Rejection
Claims 1, 7, 17, 20, 54, 57, and 58 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all disclosed in the specification to possess at least one property in common which is mainly responsible for their function in the claimed relationship, and it is clear from their very nature or from the prior art that all of them possess this property. Second, where a Markush grouping describes alternative chemical compounds, the members of a proper group there should share (1) a common utility and (2) a substantial structural feature essential to that utility. See MPEP § 803.02 and 2117.
The Markush grouping of claims 1 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: All of the members of each group do not appear to share a common utility that is required for any shared function. Thus, the groups are improper and the claims are rejected due to a lack of a common function and/or a common substantial structure feature that is essential to a common function.
The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial structural feature and a common use that flows from the substantial structural feature for the following reasons:
Regarding claims 1 and 58, a person having ordinary skill in the art would readily appreciate that chimeric antigen receptor (CAR) and T cell receptor (TCR) differ in their structure and function. CARs use an antibody domain to bind to an antigen, whereas TCRs use TCRα and TCRβ, which each have their own six complementarity-determining regions (CDRs). Moreover, TCRs largely cannot bind antigen on their own. They need an antigen complexed with major histocompatibility complex (MHC) molecules, wherein that complex is the TCR target. CARs and TCRs do not share a common core to bind an antigen and do not have a common function as they do not bind the same types of targets. Thus, CAR and TCR are an improper Markush group.
Regarding claim 7, a person having ordinary skill in the art would readily appreciate that interferon (IFN), foscarnet, and ganciclovir differ in their structure and function. The specification defines IFN as being a cytokine from a natural source (page 51, paragraph 0179). On the other hand, ganciclovir and foscarnet are defined as being two different small molecule inhibitors of HHV viral DNA polymerase (page 61, paragraph 0204). While ganciclovir and foscarnet share a common function, they do not share a common core structure. IFN compared to ganciclovir and foscarnet does not share a common function and/or structure. Thus, IFN, foscarnet, and ganciclovir are an improper Markush group.
Regarding claims 17, 20, 54, and 57, a person having ordinary skill in the art would readily appreciate that RNA and DNA, i.e., nucleic acids, and proteins, i.e., amino acids, differ in their structure and function. Both RNA and DNA have a common backbone structure as they are comprised of nucleic acids, whereas the backbone of proteins is composed of amino acids. There are four different nucleic acids, i.e., adenine, uracil, guanine, and cytosine for RNA and adenine, thymine, guanine, and cytosine for DNA, and 20 different amino acids. Thus, nucleic acids, i.e., RNA and DNA, versus amino acids, i.e., proteins, are an improper Markush group.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use. In light of the correspondence on 02/10/2026, Applicant should either amend the claims to recite only the elected individual species or grouping of species that share a substantial structure feature as well as a common use, or present sufficient evidence that the species recited overcome this rejection.
This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. § 134 and 37 CFR 41.31(a)(1).
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:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
Anti-HHV-6 CAR macrophages with IFNα
Claims 1, 3 – 7, 10, 16, 17, 20, 22, 24, 26, 42, 44 – 47, 49, 54, 57 – 59, and 61 are rejected under 35 U.S.C. 103 as being unpatentable over Stripecke, R., et. al., (US 20210230245 A1; Published 07/29/2021), hereby Stripecke, in view of Klichinsky, M., et. al., (US 20220000918 A1; Published 01/06/2022), hereby Klichinsky; as evidenced by Kondo, K., et. al., (Strong interaction between human herpesvirus 6 and peripheral blood monocytes/macrophages during acute infection. Journal of medical virology, 67(3), 364–369; Published 07/2002), hereby Kondo; and Fishman, J. A., et. al., (Overview: cytomegalovirus and the herpesviruses in transplantation. American journal of transplantation, 13 Suppl 3, 1–8; Published 02/2013), hereby Fishman.
Stripecke teaches the method of making an engineered immune cell, including macrophages, by culturing a host cell under conditions that allow for the expression of a CAR (abstract; page 4, paragraphs 0046 and 0047; page 21, paragraph 0191; page 22, paragraph 0194), as recited in instant claims 1 and 42. The CAR is encoded by and introduced to the immune cell as an exogenous nucleic acid sequence, for example, a vector, wherein the vector may be a lentiviral or adenoviral vector (abstract; page 4, paragraph 0045; page 8, paragraphs 0099 – 0102; page 15, paragraph 0134; page 19, paragraphs 0166 – 0171; page 20, paragraph 0176; page 21, paragraph 0188), as disclosed in instant claims 1, 22, 42, 58, and 59. This CAR-engineered immune cell is employed for the treatment of a herpes virus, including human herpesvirus 6 (HHV-6), wherein the occurrence or recurrence of the disease state is prevent, inhibited, or reduced (page 3, paragraph 0041; page 4, paragraph 0054; page 14, paragraph 0114; page 24, paragraph 0217), as defined in instant claims 1 and 42. Stripecke goes on to teach that the immune cells themselves can be isolated from an individual in need of therapy, i.e., a patient, or a seronegative donor, i.e., a healthy subject (page 4, paragraphs 0044 and 0053; page 22, paragraph 0195; page 24, paragraph 0215), as defined in instant claims 24 and 61. It is further taught that the CAR itself is designed to target a sub-set of herpes virus antigens that are present on the surface of latently infected cells and the immune cells are obtained from an autologous source, i.e., the immune cells themselves have latent HHV-6 infection (page 2, paragraphs 0017, 0021, and 0022; page 21, paragraphs 0190 and 0192; claim 1), as disclosed in instant claims 1, 26, and 42.
Stripecke teaches that the CAR-engineered immune cell could be engineered to additionally co-express cytokines, such as interferon alpha (IFNα), to improve immune therapeutic effects (page 4, paragraph 0048). However, Stripecke does not teach contacting the immune cells with an antiviral agent by adding the agent into the culture medium, as defined in instant claims 1 and 42, wherein the antiviral agent is IFN, as required in instant claims 7 and 49.
Klichinsky teaches a method of increasing tumor killing activity of macrophages comprising CAR by culturing the immune cell with a cytokine, including IFNα (page 1, paragraph 0008; page 23, paragraph 0212; page 30, paragraphs 0268 and 0270), as required in instant claims 1, 7, 42, and 49. It is further taught that the IFN can be added before or after delivery of an mRNA, i.e., the CAR, to the immune cell, or co-expressed with a CAR (page 23, paragraph 0211; page 30, paragraphs 0267 and 0269), as defined in instant claims 1 and 42.
Claim 16 is drawn to the intended result of the engineered immune cells having comparable levels of TCM and TSCM as compared to control cells that have not been contacted with the antiviral agent. The court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). See MPEP § 2111.04.
The “wherein” clause of claim 16 simply expresses the intended result of the process step of claim 1, upon which claim 16 depends. Therefore, a prior art reference that teaches the embodiments of claim 1, would make claim 16 obvious, i.e., Stripecke and Klichinsky.
Stripecke and Klichinsky do not explicitly teach the timing of the addition of the antiviral agent, i.e., IFN, to the culture medium, as recited in instant claims 3 – 6 and 44 – 47, and concentration of the IFN that is added, as defined in instant claims 10 and 49. However, Klichinsky teaches that there is a dose-dependent effect on CAR expression and activity upon addition of IFNα, IFNβ, and IFNγ to the culture medium (example 8, page 35, paragraphs 0313 and 0314; example 9, pages 35 and 36, paragraphs 0315 – 0322; see also figures 121A – F). Thus, the concentration of the IFN, when the IFN is added, and the duration of IFN treatment is clearly a result effective parameter that a person having ordinary skill in the art would routinely optimize in CAR-macrophage production. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
It was known in the art prior to filing of the instant application that HHV-6 infects macrophages/monocytes. Kondo teaches that macrophages/monocytes are the dominant cell population that is responsible for HHV-6 viremia during acute HHV-6 infection and the sites of HHV-6 latency (page 364, left column, abstract, right column, second paragraph; page 365, left column, first paragraph). This interaction of HHV-6 with macrophages/monocytes is partly responsible for the pathogenesis of the virus (page 364, abstract). It is further taught that HHV-6 can replicate in macrophages/monocytes in vitro (page 364, right column, second paragraph). Furthermore, Fishman teaches that lytic virus replication produces symptomatic disease due to destruction of virus-infected cells (page 4, left column, fourth paragraph). It is further taught that reactivation of latent virus from latently infected cells, i.e., macrophages, results in productive, lytic infections (page 1, abstract; page 2, table 1; page 6, left column, first and third paragraph).
Taken together, it would have been prima facia obvious to a person having skill in the art before the filing of the instant application that anti-HHV-6 CAR macrophages could have been produced to help treat HHV-6 viremia, as required in instant claims 1 and 42. Additionally, it would have been clearly advantageous to detect infection of autologous macrophages and, in turn, suppress viral replication during anti-HHV-6 CAR macrophage production in vitro to prevent destruction to the cells. While Stripecke does not explicitly teach the detection of HHV-6 DNA or RNA via PCR, ELISA, RT-PCR, or flow cytometry, as required in instant claims 17, 20, 54, and 57, it would have been prima facia obvious to a person having ordinary skill in the art to have applied this technique to detect HHV-6 in the culture medium (Stripecke; page 5, paragraph 0064; page 14, paragraph 0114; page 25, paragraph 0232; page 28, paragraphs 0244 and 0245; page 29, paragraph 0248; page 29, paragraph 0250; see also figures 2 and 3) in view of the teachings of Kondo and Fishman.
Stripecke, Klichinsky, Kondo, and Fishman are considered to be analogous to the claimed invention because both Stripecke and Klichinsky are drawn to methods to produced CAR-engineered immune cells for treatment against viral infections, wherein Kondo and Fishman provide evidence for designing anti-HHV-6 CAR macrophages. Based on the prior art teachings, it would have been obvious to a person having ordinary skill in the art to add the IFNα as the cytokine, as taught by Klichinsky, into the culture medium containing the CAR-engineered immune cells to prevent or inhibit HHV-6 infection or reactivation, as taught by Stripecke. Thus, it would have been obvious to a person having ordinary skill in the art to have combined the teachings of Stripecke and Klichinsky in view of the teachings of Kondo and Fishman before the effective filing date of the claimed invention with a reasonable expectation of success to develop a new therapeutic optimized to target an antigen (Klichinsky; page 1, paragraph 0003), wherein the antigen is HHV-6 to address medical disorders associated with it (Stripecke; page 1, paragraph 0010). All the claimed elements were known in the prior art. A person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention as there was some teaching, suggest, or motivation in the prior art or in the knowledge generally available to one of ordinary skill in the art to modify the reference or combine reference teachings, and the modification or combination would have a reasonable expectation of success. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415–421, 82 USPQ2d 1385, 1395–97 (2007) and MPEP §§ 2143G and 2143.02.
Claims 27 and 63 are rejected under 35 U.S.C. 103 as being unpatentable over Stripecke, R., et. al., (US 20210230245 A1; Published 07/29/2021), hereby Stripecke, in view of Klichinsky, M., et. al., (US 20220000918 A1; Published 01/06/2022), hereby Klichinsky; as evidenced by Kondo, K., et. al., (Strong interaction between human herpesvirus 6 and peripheral blood monocytes/macrophages during acute infection. Journal of medical virology, 67(3), 364–369; Published 07/2002), hereby Kondo; and Fishman, J. A., et. al., (Overview: cytomegalovirus and the herpesviruses in transplantation. American journal of transplantation, 13 Suppl 3, 1–8; Published 02/2013), hereby Fishman, as applied to claims 1, 3 – 7, 10, 17, 20, 22, 24, 26, 42, 44 – 47, 49, 54, 57 – 59, and 61 above, and further in view of Jaworska, J., Gravel, A., & Flamand, L., (Divergent susceptibilities of human herpesvirus 6 variants to type I interferons. PNAS, 107(18), 8369–8374; Published 04/19/2010; Cited in Applicant’s IDS on 02/23/2024 as Non-Patent Literature Cite No. 6), hereby Jaworska.
Stripecke, Klichinsky, Kondo, and Fishman do not teach that the IFNα is a human IFNα, as required in instant claims 27 and 63.
However, Jaworska teaches that the cells were treated with human IFNα (page 8374, left column, lines 9 and 10). Thus, it would be prima facia obvious to a person having skill in the art to use human IFNα to closely mimic human cell signaling and the results would be predictable as an IFNα is taught in the art and human IFNα is an IFNα, as defined in instant claims 27 and 63.
Anti-HHV-6 CAR-T cells with IFNα
Claims 1, 3 – 7, 10, 14, 16, 17, 20, 22, 24, 26, 17, 42, 44 – 47, 49, 53, 54, 57 – 59, 61, and 63 are rejected under 35 U.S.C. 103 as being unpatentable over Stripecke, R., et. al., (US 20210230245 A1; Published 07/29/2021), hereby Stripecke, in view of Jaworska, J., Gravel, A., & Flamand, L., (Divergent susceptibilities of human herpesvirus 6 variants to type I interferons. PNAS, 107(18), 8369–8374; Published 04/19/2010; Cited in Applicant’s IDS on 02/23/2024 as Non-Patent Literature Cite No. 6), hereby Jaworska; and evidenced by Lareau, C. A., et. al., (Latent human herpesvirus 6 is reactivated in chimeric antigen receptor T cells, bioRxiv; Published 08/12/2022; Cited in Applicant’s IDS on 02/23/2024 as Non-Patent Literature Cite No. 8), hereby Lareau.
Stripecke teaches the method of making an engineered immune cell, including T cells and natural killer (NK) cells, by culturing a host cell under conditions that allow for the expression of a CAR (abstract; page 4, paragraphs 0046 and 0047; page 21, paragraph 0191; page 22, paragraph 0194), as recited in instant claims 1 and 42. The CAR is encoded by and introduced to the immune cell as an exogenous nucleic acid sequence, for example, a vector, wherein the vector may be a lentiviral or adenoviral vector (abstract; page 4, paragraph 0045; page 8, paragraphs 0099 – 0102; page 15, paragraph 0134; page 19, paragraphs 0166 – 0171; page 20, paragraph 0176; page 21, paragraph 0188), as disclosed in instant claims 1, 22, 42, 58, and 59. This CAR-engineered immune cell is employed for the treatment of a herpes virus, including human herpesvirus 6 (HHV-6), wherein the occurrence or recurrence of the disease state is prevent, inhibited, or reduced (page 3, paragraph 0041; page 4, paragraph 0054; page 14, paragraph 0114; page 24, paragraph 0217), as defined in instant claims 1 and 42. Stripecke goes on to teach that the immune cells themselves can be isolated from an individual in need of therapy, i.e., a patient, or a seronegative donor, i.e., a healthy subject (page 4, paragraphs 0044 and 0053; page 22, paragraph 0195; page 24, paragraph 0215), as defined in instant claims 24 and 61. It is further taught that the CAR itself is designed to target a sub-set of herpes virus antigens that are present on the surface of latently infected cells and the immune cells are obtained from an autologous source, i.e., the immune cells themselves have latent HHV-6 infection (page 2, paragraphs 0017, 0021, and 0022; page 21, paragraphs 0190 and 0192; claim 1), as disclosed in instant claims 1, 26, and 42.
Stripecke teaches that the CAR-engineered immune cell could be engineered to additionally co-express cytokines, such as interferon alpha (IFNα), to improve immune therapeutic effects (page 4, paragraph 0048). However, Stripecke does not teach contacting the immune cells with an antiviral agent by adding the agent into the culture medium, as defined in instant claims 1 and 42, wherein the antiviral agent is IFN, as required in instant claims 7 and 49, specifically, human IFNα, as disclosed in instant claims 27 and 63, and the cells are T cells, as defined in instant claims 14 and 53.
However, Jaworska teaches that addition of human IFNα to SupT1 cells, which is a T-lymphoblast cell line, had a pronounced antiviral effect on HHV-6A (page 8369, abstract; page 8373, right column, bottom lines; page 8374, lines 1 – 11), as defined in instant claims 1, 7, 14, 27, 42, 49, 53, and 63. It is further taught that HHV-6 is cultured in the SupT1 cells over extended periods of time before assessing the anti-HHV-6 effects of IFNα, wherein IFNα interferes with infection processes before infection of both HHV-6 variants (page 8369, right column, first paragraph; page 8373, left column, third paragraph). However, administration of IFNα after infection did not have antiviral effects on HHV-6B, but severely impaired the growth of HHV-6A (page 8369, right column, first paragraph; page 8373, left column, third paragraph). Jaworska also teaches that gene expression of HHV-6 can be monitored with PCR, i.e., RT-qPCR.
Claim 16 is drawn to the intended result of the engineered immune cells having comparable levels of TCM and TSCM as compared to control cells that have not been contacted with the antiviral agent. The court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). See MPEP § 2111.04.
The “wherein” clause of claim 16 simply expresses the intended result of the process step of claim 1, upon which claim 16 depends. Therefore, a prior art reference that teaches the embodiments of claim 1, would make claim 16 obvious, i.e., Stripecke and Jaworska.
Stripecke and Jaworska do not explicitly teach the timing of the addition of the antiviral agent, i.e., IFN, to the culture medium, as recited in instant claims 3 – 6 and 44 – 47, and concentration of the IFN that is added, as defined in instant claims 10 and 49. However, Jaworska teaches the addition of 10 to 1,000 units/mL of IFNα to the cell culture before and after HHV-6 infection (page 8370, figure 1; page 8371, figure 2D; page 8374, left column, lines 9 – 11). Thus, the concentration of the IFN, when the IFN is added, and the duration of IFN treatment is clearly a result effective parameter that a person having ordinary skill in the art would routinely optimize in CAR-macrophage production. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
It was known in the art prior to filing of the instant application that latent HHV-6 is reactivated in CAR T cells. Lareau teaches that HHV-6 nucleic acid can become more abundant in CAR-T cell cultures over time (page 4, second paragraph; page 2, figure 2). This is because CAR-T cell cultures have rare HHV-6+ cells, termed super-expressors, that allow HHV-6 lytic reactivation of the virus to spread rapidly and overtake the cell culture (page 4, bottom paragraph; page 5, first and second paragraph). Ultimately, it is taught that CAR-T cell therapy is directly linked as a potential cellular reservoir of lytic HHV-6 that allows for rapid expansion of the virus, albeit rare, wherein longitudinal viral screening is warranted in patients receiving cell therapies (page 7, second paragraph; page 8, second paragraph).
Taken together, it would have been prima facia obvious to a person having skill in the art before the filing of the instant application that anti-HHV-6 CAR-T cells inoculated with IFNα could have been produced to help treat HHV-6 viremia, wherein administration of IFNα to the culture before infection would help prevent CAR-T cell reactivation of HHV-6, as required in instant claims 1 and 42. It also would have been obvious to detect HHV-6 levels using techniques known in the art, i.e., PCR, over the course of treatment and to ensure HHV-6 DNA or RNA levels remained stable. Furthermore, it would have clearly been advantageous to detect infection of the T cells and, in turn, suppress viral replication during anti-HHV-6 CAR production in vitro to prevent destruction to the cells.
Stripecke, Jaworska, and Lareau are considered to be analogous to the claimed invention because Stripecke is drawn to methods to produced CAR-engineered immune cells for treatment against viral infections, wherein Jaworska and Lareau provide evidence for designing anti-HHV-6 CAR-T cells with IFNα. Based on the prior art teachings, it would have been obvious to a person having ordinary skill in the art to add the human IFNα as the antiviral agent, as taught by Jaworska, into the culture medium containing the CAR-engineered immune cells to prevent or inhibit HHV-6 infection or reactivation, as taught by Stripecke and Lareau. Thus, it would have been obvious to a person having ordinary skill in the art to have combined the teachings of Stripecke, Jaworska, and Lareau before the effective filing date of the claimed invention with a reasonable expectation of success to develop a new therapeutic optimized to address medical disorders associated with HHV-6 (Stripecke; page 1, paragraph 0010). All the claimed elements were known in the prior art. A person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention as there was some teaching, suggest, or motivation in the prior art or in the knowledge generally available to one of ordinary skill in the art to modify the reference or combine reference teachings, and the modification or combination would have a reasonable expectation of success. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415–421, 82 USPQ2d 1385, 1395–97 (2007) and MPEP §§ 2143G and 2143.02.
Claims 23 and 60 are rejected under 35 U.S.C. 103 as being unpatentable Stripecke, R., et. al., (US 20210230245 A1; Published 07/29/2021), hereby Stripecke, in view of Jaworska, J., Gravel, A., & Flamand, L., (Divergent susceptibilities of human herpesvirus 6 variants to type I interferons. PNAS, 107(18), 8369–8374; Published 04/19/2010; Cited in Applicant’s IDS on 02/23/2024 as Non-Patent Literature Cite No. 6), hereby Jaworska; and evidenced by Lareau, C. A., et. al., (Latent human herpesvirus 6 is reactivated in chimeric antigen receptor T cells, bioRxiv; Published 08/12/2022; Cited in Applicant’s IDS on 02/23/2024 as Non-Patent Literature Cite No. 8), hereby Lareau, as applied to claims 1, 3 – 7, 10, 14, 16, 17, 20, 22, 24, 26, 17, 42, 44 – 47, 49, 53, 54, 57 – 59, 61, and 63 above, and further in view of Kruse, R. L., et. al., (US 20190307798 A1; Published 10/10/2019), hereby Kruse.
Stripecke teaches that the CAR-engineered immune cells can be edited for the deletion of T-cell receptors (TCR) to reduce and/or eliminate cytotoxicity (page 3, paragraph 0044; page 4, paragraph 0049). Thus, Stripecke, Jaworska, and Lareau do not teach the modification of one or both T-cell receptor alpha chain (TCRα) genetic loci to reduce or eliminate the activity of the gene, as required in instant claims 23 and 60.
However, Kruse teaches that the immune cell is modified such that the levels of one or more components of the TCRα gene are reduced to decrease cytotoxicity (page 1, paragraph 0009; page 14, paragraph 0130; claims 35 – 37), as recited in instant claims 23 and 60.
Stripecke, Jaworska, Lareau, and Kruse are considered to be analogous to the claimed invention because Stripecke and Kruse are both drawn to methods to produced CAR-engineered immune cells for treatment against viral infections, wherein Jaworska and Lareau provide evidence for designing anti-HHV-6 CAR-T cells with IFNα. Based on the prior art teachings, it would have been obvious to a person having ordinary skill in the art to add the human IFNα as the antiviral agent, as taught by Jaworska, into the culture medium containing the CAR-engineered immune cells to prevent or inhibit HHV-6 infection or reactivation, as taught by Stripecke and Lareau, wherein the TCRα gene is specifically modified, as taught by Kruse. Thus, it would have been obvious to a person having ordinary skill in the art to have combined the teachings of Stripecke, Jaworska, Lareau, and Kruse before the effective filing date of the claimed invention with a reasonable expectation of success to have CARs with reduced cytotoxicity that are safer (Kruse; title; abstract; page 15, paragraph 0144). All the claimed elements were known in the prior art. The use of a known technique to improve similar devices (methods or products) in the same way is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415–421, 82 USPQ2d 1385, 1395–97 (2007) and MPEP §§ 2143C and 2143.02.
Conclusion
Claims 1, 3 – 7, 10, 14, 16, 17, 20, 22 – 24, 26, 27, 42, 44 – 47, 49, 53, 54, 57 – 61, and 63 are rejected. No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Du, L., et. al., (IL-21 Optimizes the CAR-T Cell Preparation Through Improving Lentivirus Mediated Transfection Efficiency of T Cells and Enhancing CAR-T Cell Cytotoxic Activities. Frontiers in molecular biosciences, 8, 675179; Published 06/04/2021), teaches anti-CD3/CD28 activation of CAR-T cells transfected with a lentivirus vector, which is claimed as an option in instant claims 5 and 46.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Reymen, D., et. al., (Antiviral activity of selected acyclic nucleoside analogues against human herpesvirus 6. Antiviral research, 28(4), 343–357; Published 12/1995; Cited in Applicant’s IDS on 02/23/2024 as Non-Patent Literature Cite No. 14), teaches the addition of antiviral agents, including ganciclovir and foscarnet, to HSB-2 cells, which are a T-lymphoblastoid cell line, that are infected with HHV-6.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Hallie N. Pennington, Ph.D. whose telephone number is (571)272-6781. The Examiner can normally be reached M-Th 7:30-5:30 ET.
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/HALLIE N. PENNINGTON, PH.D./Examiner, Art Unit 1671
/Michael Allen/Supervisory Patent Examiner, Art Unit 1671