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 .
Applicant's amendments to the claims filed on 01-14-2025 have been received and entered. Claims 18, 21-23, 25 have been amended. Claims 1-25 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-21, in the reply filed on 06-11-2026 is acknowledged.
Claims 22-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06-11-2026.
Claims 1-21 are under consideration.
Priority
This application is a 371 of PCT/US2023/027819 filed on 07/14/2023 that claim priority from US provisional application 63/496,594 filed on 04/17/2023, and US provisional application 63/483,167 filed on 02/03/2023, and US provisional 63/381,464 filed on 10/28/2022, and US provisional 63/373,281 filed on 08/23/2022 and is a CON of 17/812,521 filed on 07/14/2022.
The effective filing date of the instant claims is 07/14/2023 because the applications 63/496,594; 63/483,167; 63/381,464; 63/373,281; and 17/812,521 do not disclose every limitations in the instant claims (e.g., “blood exchange module”, “blood processing module”, “cell processing module”, “the blood exchange module comprises a first outlet port with a tube connecting to the blood processing module”, “the blood processing module comprises a first outlet port with a tube connecting to the cell processing module”, “the cell processing module comprises an optional outlet port with a tube connecting
to the blood exchange module” etc.).
This application repeats a substantial portion of prior Application No. 17/812,521, filed on 07/14/2022, and adds disclosure not presented in the prior application. Because this application names the inventor or at least one joint inventor named in the prior application, it may constitute a continuation-in-part of the prior application. Should applicant desire to claim the benefit of the filing date of the prior application, attention is directed to 35 U.S.C. 120, 37 CFR 1.78, and MPEP § 211 et seq. The presentation of a benefit claim may result in an additional fee under 37 CFR 1.17(w)(1) or (2) being required, if the earliest filing date for which benefit is claimed under 35 U.S.C. 120, 121, 365(c), or 386(c) and 1.78(d) in the application is more than six years before the actual filing date of the application.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01-14-2025 are in compliance with the provisions of 37 CPR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Objections
Claims 14-15, 19-20 are objected to because of the following informalities:
Claim 14 recites the phrase “SEQ ID NO: 164184”. However, since there is no “SEQ ID NO: 164184” listed in sequence listing, it appears the “SEQ ID NO: 164184” is “SEQ ID NO: 84” as recited in claim 19.
Claim 19 is objected to because it is somewhat grammatically clumsy and difficult to interpret due to the phrase “A viral particle comprising or a polynucleotide encoding SEQ ID NO:…” On the one hand, the claim appears to have typographical error with an extra “or” in the claim such that the claim is intended to be limited to embodiments where the viral particle comprises a polynucleotide encoding one or more of the recited proteins. On the other hand, one could interpret claim 19 as being intended to comprise the “or” between the words “comprising” and “a” and to encompass two different types of viral particles: (i) a viral particle comprising one or more of proteins comprising one of the recited amino acid sequences; and (ii) a particle comprising a nucleic acid encoding one or more proteins comprising one of the recited amino acid sequences. Upon review the instant specification, it appears Applicant may intend the latter interpretation (e.g., see items 92 and 96 at page 82 of the instant disclosure). In which case, it would add clarity to the claim language to amend it such that both alternatives are more clearly recited (e.g., “Claim 19. A viral particle comprising one or more polypeptides comprising the sequence of one of SEQ ID NO: 72, SEQ ID NO:73, SEQ ID NO: 74, SEQ ID NO:84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 82, OR a viral particle comprising a polynucleotide encoding the sequence of one or more of SEQ ID NO: 72, SEQ ID NO:73, SEQ ID NO: 74, SEQ ID NO:84, SEQ ID NO: 85, SEQ ID NO: 86, and SEQ ID NO: 82.”).” Alternatively, if the “or” in line 1 of claim 19 is a typographical error, it would be remedial to amend claim 19 to read something like, “A viral particle comprising the amino acid sequence of SEQ ID NO: 72,…”.
Claims 14-15, 19-20 are objected to for the way the sequence identifiers (i.e., SEQ ID NOS) are being used. A sequence identifier merely describes a particular amino acid or nucleic acid sequence. It is not the sequence itself. Thus, a viral particle or cell cannot logically comprise a SEQ ID NO. Rather, it may comprise the amino acid sequence of SEQ ID NO: X or the polynucleotide sequence of SEQ ID NO: Y. Accordingly, it would be remedial to amend the following claims to clearly refer to the amino acid or nucleic acid sequence of the corresponding SEQ ID NO. For example:
Regarding to claim 15, the phrase “The system of claim 1, wherein the one or more viral particles comprise SEQ ID NO: 88 or SEQ ID NO: 90” could reasonably be amended to read “The system of claim 1, wherein the one or more viral particles comprise a nucleic acid comprising the polynucleotide sequence of SEQ ID NO: 88 or SEQ ID NO: 90”. Similarly, claim 14 could reasonably be amended to read “The system of claim 1, wherein the one or more viral particles comprise a nucleic acid encoding a polypeptide comprising the amino acid sequence of SEQ ID NO….” (it is noted that the sequences of the sequence identifiers SEQ ID NOs in claim 14 appear to be not protein sequences of viral proteins but they are binding proteins, such as SEQ ID NO: 86 is a CD80 binding protein linked to an anti-CD3 binding protein)
Regarding claim 20, it could be amended to read as follows: “A viral particle comprising the sequence of SEQ ID NO: 88 or SEQ ID NO: 90”.
Appropriate correction is required.
Specification
The disclosure is objected to because of the following informalities:
There’s no sequence identifier SEQ ID NO: 164184 in the sequence listing. However, the instant specification recites “sequence identifier SEQ ID NO: 164184” twice in the exemplary embodiments (see page 82, items 92 and 96 of the exemplary embodiments). It appears the sequence identifier SEQ ID NO: 164184 is supposed to be ‘SEQ ID NO: 84’ (e.g., claim 19).
Appropriate correction is required.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
Claims 1, 18 are being interpreted under 35 U.S.C. 112(f).
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
In the instant case, claims 1, 18 are being interpreted under 35 U.S.C. 112(f) for the following reasons:
Regarding (A), the claim limitations use a term “module” in claim 1 and “configured” in claim 18 that are a generic placeholder for performing the claimed function.
Regarding (B), the generic placeholder is modified by functional language : “module for collecting blood from a subject and optionally for infusing blood back into the subject” and “module for separating blood components to obtain selected blood cells from the rest of the blood” and “module for transducing the selected blood cells with one or more viral particles comprising one or more cell-activating agents;” in claim 1; and “configured to operate in a closed and automatic manner” in claim 18.
Regarding (C), the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Therefore, regarding claims 1, 18, the phrases “module for collecting blood from a subject and optionally for infusing blood back into the subject” and “module for separating blood components to obtain selected blood cells from the rest of the blood” and “module for transducing the selected blood cells with one or more viral particles comprising one or more cell-activating agents;” in claim 1; and “configured to operate in a closed and automatic manner” in claim 18 are interpreted as a means-function limitation under 35. U.S.C. 112f because it contains the generic placeholders “module” and “configured” that are modified by the functional language and are not modified by sufficient structure, material, or acts for performing the claimed function because there are no other elements recited in the claim.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 11-17 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 11-17 do not satisfy the requirements of 112(d), as they contain a reference to a previous claims but do not specify a further limitation of the subject matter claimed. Specifically, Claim 1 is directed to a cellular therapeutic system, and the dependent claims 11-17 directed to viral particles do not specify or require the viral particle to be present in the system recited in claim 1. The phrase “for transducing the selected blood cells with one or more viral particles” recited in claim 1 is intended use for “cell processing module” and does not structurally or functionally modify cellular therapeutic system. Claims 11-17 do not specify or require the viral particle present in the “cell processing module”. The claims 11-17 do not recite structural limitation to further limit the claimed “cellular therapeutic system” recited in claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 11-17, and 21 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 11-17 are vague and indefinite because it's not clear how these dependent claims further limit the system as recited in claim 1. For example, claim 1 and these dependent claims do not require that the recited viral particles/cells are present in the system. It's unclear how the recited viral particles functionally and/or structurally affect the recited “a cellular therapeutic system” of claim 1, which appears to be an apparatus.
Claim 21 is vague and indefinite regarding the phrase “one or more viral particles comprising a CAR and optionally, wherein the CAR binds a solid tumor antigen”. Based on the plain language of the claim, the phrase can be interpreted such that the viral particles are expressing and having (comprising) a CAR polypeptide (a receptor) on their envelope surface and may be capable of binding to a solid tumor antigen. However, this interpretation is not necessarily consistent with the instant disclosure. The instant specification teaches that “a viral vector comprising a nucleic acid encoding a CAR molecule such that cells, organs or tissues of the peripheral vascular system of the subject express the CAR molecule” (see [00196], page 34), and “the vectors described herein comprise a nucleic acid sequence encoding a binding molecule. In embodiments, the binding molecule is a CAR or TCR. In embodiments, the vector is a lentiviral vector” ([00279], page 50) and “The T cells are subsequently contacted with a lentiviral particle to facilitate their infection, leading to the integration of the nucleic acid into the T cells' genome …. and the infected T cells express one or more CARs” (see [00418], page 72-73). Thus, it appears the instant specification teaches infection of lymphocytes such as T- cell by lentiviral vectors to express CARs in the cells rather than the viral particle itself comprising CARs. Therefore, there appears to be an inconsistency between the teachings of the instant disclosure and the plain language of claim 21 that makes the metes and bounds of what’s actually encompassed by the claim indefinite.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 19 is rejected under 35 U.S.C. 102(a)(2) as being anticipated by Perkins et al. (Pub. No.: US 2024/0218390 A1, Provisional application No. 63/154,639, filed on Feb. 26, 2021.).
Claim interpretation:
Claim 19 can reasonably be interpreted as encompassing two different types of viral particles: (i) particles where the particle comprises one or more proteins comprising one of the specifically recited amino acid sequences, and (ii) viral particles comprising a polynucleotide encoding one or more proteins comprising one of the specifically recited amino acid sequences.”
Regarding to claim 19, Perkins et al teach “lentiviral vectors comprising a mutated, heterologous envelope protein, a targeting protein, and at least one transgene for delivery to and expression by a cell characterized by the targeting protein” (Abstract). Perkins et al teach “In embodiments of LVV production methods that utilize a combination of five plasmids, the fifth plasmid is a targeting protein plasmid and includes an expression cassette that encodes one or more targeting proteins ….. a targeting protein plasmid includes a tandem expression cassette that comprises a polynucleotide according to SEQ ID NO: 21, which encodes a polypeptide according to SEQ ID NO: 22” ([0153], page 44). Perkins et al teach SEQ ID NO 22 which is 100% identical to SEQ ID NO: 86 of the claimed invention (see below). Thus, Perkins et al teach an embodiment of the claimed invention where the LVV particle of Perkins et al comprises a protein having the amino acid sequence of SEQ ID NO: 86.
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Thus, claims 19 is anticipated by Perkins et al.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Perkins et al. (Pub. No.: US 2024/0218390 A1, Provisional application No. 63/154,639, filed on Feb. 26, 2021.).
Regarding claim 21, as noted above Perkins et al teach an embodiment of the claimed invention where the LVV particle of Perkins et al comprises a protein having the amino acid sequence of SEQ ID NO: 86. In addition, Perkins et al teach self-inactivating lentiviral vectors (LVV) and/or CAR modified lymphocyte (e.g., T cell, B cell, or NK cell) compositions ([0178], page 48). Perkins et al teach that the LVV described herein further includes a transgene, with the LVV being capable of specifically binding to a target immune cell and transducing the target immune cell such that the transgene is expressed by the immune cell. In some embodiments, the LVV may carry more than one transgene. In further specific embodiments, the transgene encodes a chimeric antigen receptor (CAR) ([0076], page 7).
Perkins et al don’t appear to reduce to practice a single embodiment comprising both types of viral particles.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify and combine the method of Perkins et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Perkins et al teach “The LVV described herein can be used to modify targeted lymphocytes (e.g., T cells, B cells, or NK cells) to express a CAR encoded by a transgene carried by the LVV….. In such embodiments, the engineered lymphocytes (e.g., T cells, B cells, or NK cells) express a CAR encoded by the transgene carried by the LVV. These lymphocytes are also referred to herein as "CAR modified lymphocytes.” (see [0159], page 45) and “the present disclosure provides methods of treating a disease in a subject comprising administering to the subject an effective amount of an LVV as described herein, a CAR modified lymphocyte (e.g., T cell, B cell, or NK cell) as described herein” (see [0171], page 45). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Perkins et al were successful in generation of T Cells Engineered to expressing CAR construct by using LVV: “Example 3: methods for ex vitro generation of tumor-reactive t cells engineered to express a chimeric antigen receptor (CAR) using a lentiviral vector containing t cell-specific tropism” (see example 3 page 53).
Claims 1-10, 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Perritt et al. (Pub. No.: US 2014/0030238 A1, Pub. Date: Jan. 30, 2014).
Claim interpretation:
The phrase “…for transducing the selected blood cells with one or more viral particles…” is interpreted as intended use. It should be noted that a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Regarding to claim 1, Perritt et al teach “FIG. 1 is a block diagram illustrating the current means by which blood is removed from a patient, processed and returned. Here, an arrangement 100 of devices that can be sequentially used for cell collection employing leukapheresis and cell enrichment techniques, such as using cell washing, purification. The diagram also lists optional cell modifications. Exemplary devices that can be used in this method include the Cabe Spectra device. Such a device, 110, for leukapheresis (collection), is used sequentially with a cell washing device, such as a Baxter CytoMate device, 120, (enrichment) which is further used with a cell purification (enrichment) device such as a Baxter Isolex 300i device, 130. In addition, cell manipulation (modification) devices, 140, can be employed in this scheme and include, but are not limited to: electroporation, lipofection, viral transduction, light (UVA, UVB, etc.), addition of drugs, cell activation, pressure, heating functions, etc. The bag 150 of processed blood cells produced as the output of devices 110, 120, 130, and 140 are provided to the patient 160 for return of the processed blood.” ([0009], page 1) (For the claimed: a blood exchange module, a blood processing module, a cell processing module).
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Perritt et al teach “FIG. 8 is a schematic diagram of a device performing collection, enrichment, and modification in accordance with another embodiment of the present invention” ([0030], page 3, see Figure 8 above) (for the claimed: “the blood exchange module comprises a first outlet port with a tube connecting to the blood processing module for flowing the blood collected from the subject to the blood processing module; the blood processing module comprises a first outlet port with a tube connecting to the cell processing module for flowing the selected blood cells to the cell processing module, and optionally, a second outlet port with a tube connecting to the blood exchange module for flowing the rest of the blood to the blood exchange module; the cell processing module comprises an optional outlet port with a tube connecting to the blood exchange module for flowing the transduced blood cells to the blood exchange module; and optionally, the blood exchange module comprises a second outlet port for infusing the transduced blood cells to the subject, and optionally for infusing the rest of the blood to the subject”).
Regarding to claim 2, Perritt et al teach “In this example, the number ofcells in the treatment
bag 791 was adjusted to 1x109, ….. This incubation and circulation last at least 30 minutes, with mixing or agitation of the Treatment Bag 737 and the Plate 778…”. Thus, the treatment time through the system was recognized in the prior art to be a result-effective variable. A person of ordinary skill in the art would have been motivated to perform the treatment time a plurality of times with different treatment time out of the course of routine optimization, in order to increase the effectiveness of the treatment.
Regarding to claim 3, Perritt et al teach “Example 1: Collection of Mononuclear Cells from Peripheral Blood and Enrichment of CD4+ T-Lymphocytes. A peripheral blood bag was prepared to represent a faux patient. Four (4) units of ABO matched whole blood from healthy donors was collected into ACD-A anticoagulant, 1-2 days prior to use. The units of blood were white blood cell depleted by filtration through a Sepacell leukoreduction filter and pooled into a 2L blood bag …...” ([0093], page 9).
Regarding to claim 4, Perritt et al teach “Blood Processing System: The Therakos CellEx Photopheresis System formed the basis of the blood-processing device. As depicted in FIG. 9, the system 900 comprises several components including a centrifuge chamber 962, a pump deck 964, a photoactivation chamber, and a user-friendly software driven operator interface 960” ([0095], page 9)
Regarding to claim 5, Perritt et al teach “cell manipulation (modification) devices, 140, can be employed in this scheme and include, but are not limited to: electroporation, lipofection, viral transduction, …….” ([0009], page 1).
Regarding to claim 6, Perritt et al teach “On completion of the CellEx mononuclear cell collection, a fraction of the mononuclear cell product was washed with cell enrichment buffer and CD4+ selection beads (Dynal) were introduced at a concentration via the needle-free access port of the 'treatment bag'….” ([0105], page 10).
Regarding to claim 7 and claim 9, Perritt et al teach “…… Blood Cell Processor or the Baxter CytoMate™ Cell Washing System is often used to wash, concentrate, or place the cells into appropriate growth or infusion medium” ([0006], page 1).
Regarding to claim 8, Perritt et al teach “The cells of Example 1 or 2 can be modified in a closed fluid path as shown in FIG. 8. The enriched cells are transferred by means of a pump to the modification chamber. An agent such as a growth factor (example interlenkin-2), peptides and/or a gene delivery agent (example viral vector) is introduced and the cells maintained at constant temperature (cultured).” ([0130], page 13).
Regarding to claim 10 and claim 18, Perritt et al teach “the apparatus and the patient forming a closed loop when coupled together; and a controller for automated control of operation of the inlet and outlet interfaces, the leukapheresis module, and the enrichment module” ([0018], page 2).
Regarding to claim 17, Perritt et al teach peripheral blood mononuclear cells (PBMCs) : “Target cells are cells that are enriched from peripheral blood post bulk mononuclear cell collection….” ([0069], page 6)
While Perritt et al teach of the elements of the claimed invention, they don’t exemplify a single embodiment comprising each of the steps recited in the instant claims.
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the system of Perritt et al to generate a cellular therapeutic system for treatment of a subject as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Perritt et al teach “In accordance with a further aspect of the invention,
there is provided a system for processing blood. The system comprises: a mechanism for obtaining blood from a patient and comprises a single blood processing device coupled to the obtaining means and the patient to form a closed loop between the patient and the blood processing device. The blood processing device comprises: a module for collecting bulk mononuclear blood cells from the blood by leukapheresis implemented using the blood processing device in the closed loop; and a module for enriching concurrently target cells separated from non-target cells in the bulk mononuclear blood cells using the blood processing device in the closed loop.” ([0020], page 2), and “The embodiments of the invention efficiently carry out the process of apheresis in a patient-connected, closed-loop continuous-flow manner, whereby only target components of blood (e.g. CD34+ progenitor cells) are enriched while all other remaining components are returned to the patient. Additionally, certain other functions may be carried on the target cells (e.g. modifying the phenotype) with the option of returning the modified cells to the patient. The provision of such a device can significantly reduce operating costs (no need of multiple apparatus and consumables) and ensure product consistency. Enabling the apheresis procedure to occur in a single location in a single device also reduces the risk of damage or loss of the product” ([0035], page 3). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Perritt et al were successful in generation of an apparatus that can carry out the process of apheresis in a patient-connected, closed-loop continuous-flow manner with the option of returning the modified cells to the patient.
Claims 11-14, 16 are rejected under 35 U.S.C. 103 as being unpatentable over Perritt et al. (Pub. No.: US 2014/0030238 A1, Pub. Date: Jan. 30, 2014) in view of Perkins et al (Pub. No.: US 2024/0218390 A1, Provisional application No. 63/154,639, filed on Feb. 26, 2021.).
The teachings of Perritt et al above are incorporated herein in their entirety.
Although Perritt et al teach modification to generate cytotoxic T lymphocytes targeted to a specific cancer ([0066], page 6) and transducing the blood cells with viral particles, Perritt et al do not teach viral particles comprise one or more polynucleotides encoding chimeric antigen receptors (CARs) and viral particles comprising one or more cell-activating agents cell-activating agents. Perkins et al cure the deficiency.
Regarding to claim 11, Perkins et al teach “lymphocyte targeted lentiviral vectors” (title) and “the present disclosure provides self-inactivating lentiviral vectors ("LVV") that include a viral envelope comprising a mutated, heterologous envelope protein and a tropism defining molecule (also referred to as a "targeting protein"). …. In some embodiments, the LVV may carry more than one transgene. In further specific embodiments, the transgene encodes a chimeric antigen receptor (CAR) ([0076], page 7).
Regarding to claim 12-13, Perkins et al teach “The targeting protein is a membrane-bound protein displayed on the viral envelope and includes an extracellular domain that includes a lymphocyte targeting domain and a transmembrane domain. A lymphocyte targeting domain is any protein or peptide that has an amino acid sequence and is a binding partner for a target molecule or ligand (e.g., a cognate protein or ligand) on a target lymphocyte cell surface” ([0087], page 8-9), and “In some embodiments, lentiviral vectors comprising a CD80 targeting protein exhibit enhanced transduction CD4 T cells over CD8 T cells as a relative percentage of total CD4 and CD8 T cells compared to the transduction by standard LVV” ([0102], page 11), and “In some embodiments, the targeting protein is an anti-CD3 targeting protein. In some embodiments, an anti- CD3 targeting protein is an antibody or binding fragment thereof, including for example, a scFv” ([0103], page 11).
Regarding to claim 14, Perkins et al teach “lentiviral vectors comprising a mutated, heterologous envelope protein, a targeting protein, and at least one transgene for delivery to and expression by a cell characterized by the targeting protein” (Abstract). Perkins et al teach “self-inactivating lentiviral vectors (LVV) as described herein were produced using a third-generation production system. An expression plasmid that contains the gene sequences desired for delivery by the LVV was combined at defined ratios with three packaging plasmids, VSVG, GagPol, and Rev, and used to transfect HEK293 producer cells. Productive viral particles were harvested from the HEK293 culture media 2-3 days later. ….” ([0217], page 52). Perkins et al teach “the tandem expression cassette of the VSV-G env plasmid encodes an anti-CD3 targeting protein and a mutated VSV-G envelope protein. For example, in a specific embodiment, the tandem expression cassette may comprise a polynucleotide that has at least ... 100% identity to SEQ ID NO: 67, which encodes an amino acid sequence that has at least 100% identity to SEQ ID NO: 68 …...” ([0134], page 26). Perkins et al teach SEQ ID NO 68 which is 100% identical to SEQ ID NO: 87 of the claimed invention (see below).
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Regarding to claim 16, Perkins et al teach “Self-inactivating lentiviral vectors (LVV) as described herein were produced using a third-generation production system. An expression plasmid that contains the gene sequences desired for delivery by the LVV was combined at defined ratios with three packaging plasmids, VSVG, GagPol, and Rev, and used to transfect HEK293 producer cells” ([0217], page 52).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the cellular therapeutic system of Perritt et al by using viral particles comprising one or more cell-activating agents as taught by Perkins et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Perkins et al teach “Compared to standard lentiviral vectors (LVV) that use common third generation packaging systems, LVV packaged to redirect tropism as provided herein may have improved transduction efficiencies and specificity. The levels of available viral particles are likely increased when transducing a specific cell type as part of a heterogeneous mixture, as the LVV particles are not taken up by other, non-desired cell types” ([0224], page 53), and “the lentiviral vectors described herein are capable of selectively targeting and efficiently transducing resting lymphocytes, e.g., T cells. In some embodiments, lentiviral vectors described herein are capable of transducing and/or activating T cells in the absence of an exogenous T cell stimulating agent. In some embodiments, lentiviral vectors described herein enhance transduction of CD4 T cells compared to standard lentiviral vectors” ([0017], page 2). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Perkins et al were successful in selectively targeting and efficiently transducing resting lymphocytes with lentiviral vectors and enhancing transduction of CD4 T cells compared to standard lentiviral vectors.
Claims 1-13, 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Xiao et al. (WO 2021/226438 Al, Pub. Date: Jan. 30, 2014, International Publication Date: 11 November 2021) (Applicants’ own work).
Regarding to claim 1, Xiao et al teach “a system for immune therapy, the system comprising a sample processing module configured to obtain whole blood from a subject; a cell incubation module configured to activate blood cells of the whole blood and/ or introduce a vector into the blood cells of the whole blood; and a cell infusion module configured to infuse at least a portion of the whole blood to the subject, wherein the blood cells comprise CD3+ cells, NK cells, myeloid cells, and neutrophils” (Abstract) and “Embodiments relate to an apparatus for sample processing, the apparatus comprising: an input port configured to receive blood sample from a subject; a sample separation module configured to isolate desired cells from the blood sample, an output port configured to: flow the isolated desired cells for further processing, and return the rest of the cells and/or remaining components of the blood sample to the subject” ([00178], page 27)
Xiao et al teach a blood exchange module for collecting blood from a subject : “FIG. 26 shows a schematic view of a gene/cell therapy system 200, ….Collector 202 is configured to collect peripheral blood from a patient's vein. For example, collector 202 can be a blood collection bag, which is sterile and includes a blood collection needle, tube, blood collection bag, and containing anticoagulant” ([00377], page 76). Blood can be collected and obtained from the patient's peripheral blood using a blood collection bag ([00381], page 77).
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Xiao et al teach a blood processing module for separating blood components: “The sample processing module can further comprise a unit configured to obtain human cells from the peripheral blood of a subject. For example, the unit is an apheresis device in which the blood of a person is passed through an apparatus that separates out one particular constituent and returns the remainder to the circulation …. the sample separation module can purify CD3+ cells by negative selection using, e.g., the RosetteSep T cell enrichment Cocktail or positive selection using antiCD3 coupled to magnetic particles.” ([00165]-[00166], page 24) and
Xiao et al teach a cell processing module for transducing the selected blood cells with one or more viral particles: “…Reactor 204 can be configured to activate blood cells collected from the vein and introduce targeting vectors into the blood cells. Reactor 204 can include an infection bag configured to mix reagents and blood for introducing the vectors into the blood cells… Reactor 204 can further include a fluid changing module configured to change the medium after the infection is completed, remove the viral vector, and replace the buffer….” ([00378], page 76).
Xiao et al teach “….The system 200 can include collector 202, reactor 204, and infuser 206. Collector 202 is configured to collect peripheral blood from a patient's vein. For example, collector 202 can be a blood collection bag, which is sterile and includes a blood collection needle, tube, blood collection bag, and containing anticoagulant” ([00377], page 76) (For the claimed: the blood exchange module comprises a first outlet port with a tube connecting to the blood processing module for flowing the blood collected from the subject to the blood processing module).
Xiao et al teach “the sample processing module comprises: an input port configured to receive the blood sample from the subject; a sample separation module configured to: separate the CD3+ cells from remaining components of the blood sample, and collect the CD3+ cells; and an output port configured to flow the CD3+ cells to the cell incubation module” ([00171], page 26) (For the claimed: the blood processing module comprises a first outlet port with a tube connecting to the cell processing module for flowing the selected blood cells to the cell processing module).
Xiao et al teach “ The viral vector transferred to the transfection bag through an aseptic machine, and the peripheral blood moved to the infection bag through an aseptic machine. Physicians or other trained personnel …… can use an aseptic tubing to connect the infection bag to the corresponding port of the fluid change line; and can use a sterile tube to connect the return buffer bag to the corresponding port of the fluid change line” ([00381], page 77). (For the claimed: the cell processing module comprises an optional outlet port with a tube connecting to the blood exchange module for flowing the transduced blood cells to the blood exchange module).
Xiao et al teach “The cell infusion module can comprise an input port, an output port, and a rotating container. The input port can be configured to obtain the CD3+ cells from the cell incubation module …. and the output port can be configured to provide the CD+3 cell for the infusion to the subject” ([00169], page 25) (For the claimed: optionally, the blood exchange module comprises a second outlet port for infusing the transduced blood cells to the subject).
While Xiao et al teach of the elements of the claimed invention, they don’t exemplify a single embodiment comprising each of the steps recited in the instant claims.
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the system of Xiao et al to generate a cellular therapeutic system for treatment of a subject as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Xiao et al teach “in Embodiment 1500, the predetermined T1 can be 0.1-10 hours, which means that T cell activation and gene transfer can be performed within the predetermined time T1. Alternatively, T cell activation and gene transfer can be performed at the same time, as shown in Embodiments 1600 and 1700. For example, the isolated T cells can be mixed with lentivirus vectors encoding CARs and therapeutic agents and activation agents (e.g., CD3/CD28 beads). In embodiments, T cell expansion in vitro can be reduced since the therapeutic agents (e.g., IL-6, IL-12, and IFNy) can enhance cell expansion in the subject's body. In embodiments, several steps in Embodiment 1700 can be modified or removed. For example, PBMC can be mixed with lentivirus vectors and activation agents directly. Thus, either modified PMBC or isolated modified T cells can be infused back to the subject. Table 2 shows examples of vectors. The system herein can be applied to other immune therapies (e.g., TIL/TCR). Embodiments 1500-1700 can be performed by a closed and/or automated system (e.g., Cartactory (a CART Factory) in FIG. 1), which is connected to the patient during the whole process.” ([00227], page 38) and “B cells can be removed from the whole blood to reduce the risk of generation of B cell line cancer. For example, CD19 or CD20 antibodies can be incorporated into the system 200” ([00228], page 38), and “cells activated and expanded using the methods described herein, or other methods known in the art where T cells are expanded to therapeutic levels, are administered to a patient in conjunction with (e.g., before, simultaneously, or following) any number of relevant treatment modalities” ([00221], page 36). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Xiao et al were successful in generation of system and method for gene and cellular therapy.
Regarding to claim 2, Xiao et al teach “…In embodiments, if fresh cells are used, vein-to-vein times for Embodiments 1500-1700 can be completed in less than 1 hr, 12 hrs, 24 hrs, 48 hrs, or 72 hrs (including numbers in between)…” ([00227], page 38). Thus, the treatment time through the system was recognized in the prior art to be a result-effective variable. A person of ordinary skill in the art would have been motivated to perform the treatment time a plurality of times with different treatment time out of the course of routine optimization, in order to increase the effectiveness of the treatment.
Regarding to claim 3, Xiao et al teach “The system 200 can include collector 202, reactor 204, and infuser 206. Collector 202 is configured to collect peripheral blood from a patient's vein. For example, collector 202 can be a blood collection bag, which is sterile and includes a blood collection needle, tube, blood collection bag, and containing anticoagulant” ([00377], page 76).
Regarding to claim 4, Xiao et al teach “the sample processing module can further comprise a unit configured to obtain human cells from the peripheral blood of the subject. In embodiments, the unit is an apheresis device in which the blood of a person is passed through an apparatus that separates out one particular constituent and returns the remainder to the circulation of the subject” ([00179], page 27)
Regarding to claims 5-6, Xiao et al teach“…Reactor 204 can be configured to activate blood cells collected from the vein and introduce targeting vectors into the blood cells. Reactor 204 can include an infection bag configured to mix reagents and blood for introducing the vectors into the blood cells. For example, the infection bag can be sterile and include three lines, one of which is connected to a 0.1 um filter with a Luer interface. Reactor 204 can further include a fluid changing module configured to change the medium after the infection is completed, remove the viral vector, and replace the buffer. ….” ([00378], page 76).
Regarding to claim 7, Xiao et al teach “A device or system for immune therapy or causing a T cell response, the device comprising: … a cell incubation module configured to: receive the blood sample, mix the blood sample with one or more vectors and an agent that activates T cells to introduce the one or more vectors into cells of the blood sample, and wash the blood sample to remove the one or more non-transduced vectors …” ([00367], page 60) and “…The infusion buffer bag can be configured to wash cells to obtain products that can be returned. For example, the infusion buffer bag can be sterile and equipped with a buffer that can be returned…” ([00378], page 76).
Regarding to claim 8, Xiao et al teach “the cell incubation module comprises a rotating container configured to culture cells and/or grow cells. The rotating container is disposable and/or has
been sterilized” ([00175], page 26).
Regarding to claim 9, Xiao et al teach “a method of immune therapy by implementing the system…. introduce the nucleic acid sequence into the CD3+ cells; and replacing culture media of the transfected CD3+ cells with a solution suitable for infusion into the subject,…” ([00176], page 26-27).
Regarding to claim 10, Xiao et al teach “…As shown in FIG. 27, system 200 connects the fluid change line to the fluid change equipment (1) and open valve A …” ([00381], page 77)
Regarding to claim 11, Xiao et al teach “In embodiments, the vector comprises a nucleic acid sequence encoding a binding molecule (e.g., an antigen binding molecule). In embodiments, the binding molecule is a CAR or TCR. In embodiments, the vector is a lentivirus” ([00154], page 22).
Regarding to claims 12-13, Xiao et al teach “… the CD3+ cells can be stimulated with magnetic beads precoated with agonist antibodies against CD3 and CD28 at a ratio of three beads per cell…” ([00168], page 25)
Regarding to claims 16, Xiao et al teach “lentiviruses are complex retroviruses, which, in addition to the common retroviral genes gag, pol, and env, contain other genes with regulatory or structural function” ([00135], page 17).
Regarding to claim 17, Xiao et al teach “…the blood sample can be diluted using Dulbecco phosphate buffered saline (DPBS), and apheresis density gradient centrifugation can be performed by the sample separation module to obtain PBMCs containing lymphocytes….” ([00166], page 25).
Regarding to claim 18, Xiao et al teach “the system is closed and/or automatic for immune therapy” ([0005], page 1) and “Embodiments 1500-1700 can be performed by a closed and/or automated system (e.g., Cartactory (a CART Factory) in FIG. 1), which is connected to the patient during the whole process” ([00227], page 38).
Claim14 is rejected under 35 U.S.C. 103 as being unpatentable over Xiao et al (WO 2021/226438 Al, Pub. Date: Jan. 30, 2014, International Publication Date: 11 November 2021) (Applicants’ own work) in view of Perkins et al (Pub. No.: US 2024/0218390 A1, Provisional application No. 63/154,639, filed on Feb. 26, 2021.).
The teachings of Xiao et al above are incorporated herein in their entirety.
Xiao et al do not teach one or more viral particles comprise SEQ ID as recited in the claim 14. Perkins et al cure the deficiency.
Regarding to claim 14, Perkins et al teach “lentiviral vectors comprising a mutated, heterologous envelope protein, a targeting protein, and at least one transgene for delivery to and expression by a cell characterized by the targeting protein” (Abstract). Perkins et al teach “self-inactivating lentiviral vectors (LVV) as described herein were produced using a third-generation production system. An expression plasmid that contains the gene sequences desired for delivery by the LVV was combined at defined ratios with three packaging plasmids, VSVG, GagPol, and Rev, and used to transfect HEK293 producer cells. Productive viral particles were harvested from the HEK293 culture media 2-3 days later. ….” ([0217], page 52). Perkins et al teach “the tandem expression cassette of the VSV-G env plasmid encodes an anti-CD3 targeting protein and a mutated VSV-G envelope protein. For example, in a specific embodiment, the tandem expression cassette may comprise a polynucleotide that has at least ... 100% identity to SEQ ID NO: 67, which encodes an amino acid sequence that has at least 100% identity to SEQ ID NO: 68 …...” ([0134], page 26). Perkins et al teach SEQ ID NO 68 which is 100% identical to SEQ ID NO: 87 of the claimed invention (see below).
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Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the cellular therapeutic system of Xiao et al by using SEQ ID NO 68 as taught by Perkins et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Perkins et al teach “Compared to standard lentiviral vectors (LVV) that use common third generation packaging systems, LVV packaged to redirect tropism as provided herein may have improved transduction efficiencies and specificity. The levels of available viral particles are likely increased when transducing a specific cell type as part of a heterogeneous mixture, as the LVV particles are not taken up by other, non-desired cell types” ([0224], page 53), and “the lentiviral vectors described herein are capable of selectively targeting and efficiently transducing resting lymphocytes, e.g., T cells. In some embodiments, lentiviral vectors described herein are capable of transducing and/or activating T cells in the absence of an exogenous T cell stimulating agent. In some embodiments, lentiviral vectors described herein enhance transduction of CD4 T cells compared to standard lentiviral vectors” ([0017], page 2). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Perkins et al were successful in selectively targeting and efficiently transducing resting lymphocytes with lentiviral vectors and enhancing transduction of CD4 T cells compared to standard lentiviral vectors.
Conclusion
Claims 1-19 and 21 are rejected.
Claim 20 is free of the art.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
