DETAILED ACTIONNotice 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 .
Priority
This application is a CON of 15/826,671 which claims priority to a filing date of 11/29/2016.
Status of Claims
Claims 2-29 received on 04/07/2021 are currently pending and under examination.
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 21 and 22 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.
Regarding claims 21 and 22, these claims depend from claim 2. Claims 21 and 22 recite
limitations directed to assembled nucleic acids comprising full-length variable regions. These limitations are already claimed in claim 2 and therefore claims 21 and 22 fail to further limit.
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 § 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 2-29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Thomas et al. US 2019/0040381 A1 further in view of Finn et al. US 2013/0289261 A1.
Regarding claim 2, Thomas et al. discloses methods for cloning T-cell receptors (TCRs) (e.g., paired αβ and γδ TCR chains) (Thomas et al. Abstract). This is interpreted as Thomas et al. teaching methods for obtaining “a plurality” of functional T cell receptors.
Regarding step (a), Thomas et al. teaches methods for cloning T-cell receptors (TCRs) (e.g., paired αβ and γδ TCR chains) whereby single T cells (e.g., human T cell) are sorted into separate locations in a multi-well plate (e.g., 96-well; greater than 50) to generate cDNA from the RNA in these cells, nested amplification (two rounds) are performed in order to generate amplification products (first and second) that comprise various segments (e.g., Vα, Vγ, Vβ, Vδ, Jα, Jγ, Cα, Cγ, Dβ, and Dδ). (Thomas et al. [0032] and [0035]).
Regarding step (b) Thomas et al. teaches the generated amplification products are assembled into a plurality of nucleic acid expression vectors which encode functional T cell receptors (Thomas et al. Abstract, [0098]; and FIGS. 1A, 4, 5B).
PNG
media_image1.png
812
543
media_image1.png
Greyscale
Thomas et al. provides for the assembly of TCRs in vectors as comprising full-length TCR chains (e.g., αβ and γδ), Thomas et al. teaches ligating (i.e. assembly) of Valph and Vbeta or Vgamma and Vdelta nucleic acids (Fig 2A caption).
Further, Example 3 – Establishment of Human TCRαβ and TCR γδ Retroviral Expression Clone Library of Thomas et al. provides for the cloning of full-length TCR chains.
Further, Thomas et al. provides for assembled nucleic acid vectors to comprise variable regions (e.g., α, β, γ, δ) (Thomas et al. [0035], [0050], [0089], and [0098]).
Thomas et al. does not specifically teach “wherein said functional T cell receptor
comprises (i) a full-length α variable region and full-length β variable region from said single T cell or (ii) a full-length γ variable region and a full-length δ variable region from said single T cell.”
However, Finn et al. teaches a similar method directed to T-cell receptors (TCRs) along with methods for the construction of vectors comprising the T-cell receptors (Finn et al., Abstract; [0003], [0153], [0157], [0158] and [0180]). Finn et al. further teaches the design and construction of nucleic acid vectors comprising full-length variable regions (e.g., α and β) as present in a single T cell originating RNA (MA CTL clone, which is the source of the TCR) (Finn et al. Abstract, [0041], [0153], [0157], [0158] and [0180]. Fig. 10A, 14A). Finn et al. further teaches:
“This example describes the design and construction of several gene transfer vectors for expression in mammalian cells of membrane bound and soluble human T cell receptors (TCR). In particular, this example describes a vector (TCR α-IRES-β pEF4) that encodes high-level expression of a full-length TCR of the present invention on the surface of T cells. Furthermore, this example describes a chimeric TCR that does not require the presence of endogenous CD3 molecules for surface expression, which allows the receptor to be expressed on cells other than T cells. This example also describes a vector encoding a single chain TCR (scTCR) as a fusion protein of VαVβCβ with CD3ζ. Advantageously, this scTCR is well suited for gene therapy because it is encoded and expressed as a single molecule and does not require individual cells to be transduced by multiple nucleic acids. Moreover, this example describes a mammalian expression vector encoding a soluble human TCR. The approaches used in this example for manipulation of a human tumor specific TCR also can be used to study various aspects of TCR-based immunotherapy.” (Paragraph [0153])
“Cloning of Full-Length TCR α and β Chains.
MA CTL clone, the source of the TCR, is described in Magarian-Blander et al. (J. Immunol, 160: 3111-3120 (1998)). RT-PCR was performed using GeneAmp RT-PCR kit (Applied Biosystems, Foster City, Calif. USA) and using either Vα (P1) or Vβ (P2) leader sequence specific forward primers and Cα (P3) or Cβ (P4) reverse primers. The TCR α and β chains were cloned into the multiple cloning site A (MCSA) and multiple cloning site B (MCSB) in the pIRES vector (Clontech Laboratories, Palo Alto, Calif., USA). The TCRα-IRES-TCRβ cassette was then subcloned into the pEF4 mammalian expression vector (Invitrogen, FIG. 10A).” (Paragraphs [0157]-[0158])
“Thus this example describes several mammalian expression vectors useful for functional high-level expression of human TCR α and β chains that are useful for biological and biochemical analyses, as well as immunotherapy. Our TCR α-IRES-β pEF4 vector encoding the tumor antigen-specific TCR generated high levels and stable expression of the TCR αβ/CD3 complex on the surface of transfected T cells. We also constructed chimeric TCR αζ and TCR βζ that were successfully expressed on the surface of 293H cells (a non T cell line that doesn't express the CD3 complex). Additionally, we showed that surface expression of the TCR was dependent on the co-expression of the TCR αζ and TCR βζ. We hypothesized that pairing of the TCR αζ to the TCR βζ was crucial for proper folding and transport of the heterodimer through the endoplasmic reticulum (ER) and Golgi and eventually to the cell surface.” (Paragraph [0180])
It would have been obvious to one of ordinary skill in the art at the time of the invention to have modified the method for cloning T-cell receptors (TCRs) (e.g. paired αβ and γδ TCR chains) as disclosed in Thomas et al. with nucleic acid vectors comprising full-length variable regions (e.g., α, β, etc.), as disclosed by Finn et al., resulting in nucleic acid vectors comprising the full-length variable regions as present in the T cell originating RNA. One would have been motivated to have done so because Finn et al. provides one in the art some teaching, suggestion, or motivation for the construction of vectors comprising full-length variable regions by indicating such vectors: 1) are well suited for gene therapy since it is encoded and expressed by a single molecule and does not require individual cells to be transduced by multiple nucleic acids; and 2) are useful for biological and biochemical analysis, as well as immunotherapy (Finn et al., [0153], [0177], and [0180]). Furthermore, Thomas et al. and Finn et al. are directed to the construction of nucleic acid vectors comprising variable regions (e.g., α, β, etc.) and, thus, are directed to the same purpose and/or outcome.
Regarding claim 3, Thomas et al. teaches wherein the assembled nucleic acid encoding a functional T cell receptor is assembled into a nucleic acid vector. Thomas et al. (Abstract, [0011], [0015], [0024], [0032], [0035], [0040], [0045], [0050], [0061], [0089], and [0098]; and FIGS. 1A, 4, 5B).
Regarding claim 4, Thomas et al. teaches nucleic acid expression vectors which encode functional T cell receptors Thomas et al. (Abstract, [0011], [0015], [0024], [0032], [0035], [0040], [0045], [0050], [0061], [0089], and [0098]; and FIGS. 1A, 4, 5B).
Regarding claim 5, Thomas et al. teaches a 96-well plate (which is greater than 50). (Thomas et al. [0032]).
Regarding claim 6, Thomas et al. teaches a multi-well plate (Thomas et al. [0032]).
Regarding claim 7, Thomas et al. teaches single human T cells (Thomas et al. [0032]).
Regarding claim 8, Finn et al. teaches “and using either Vα (P1) or Vβ (P2) leader sequence specific forward primers and Cα (P3) or Cβ (P4) reverse primers.” (Finn et al. “Cloning of Full-Length TCR α and β Chains).
Regarding claim 9, Thomas et al. teaches cloning of various segments (e.g., Vα, Vγ, Vβ, Vδ, Jα, Jγ, Cα, Cγ, Dβ, and Dδ). (Thomas et al. Abstract, [0011], [0015], [0024], [0032], [0035], [0040], [0045], [0050], [0061], [0089], and [0098]; and FIGS. 1A, 4, 5B).
Regarding claim 10, Finn et al. teaches “and Cα (P3) or Cβ (P4) reverse primers.” (Finn et al. [0158]). This is interpreted as encoding a 5’ portion of a Cα.
Regarding claim 11, Thomas et al. teaches cloning of various segments (e.g., Vα, Vγ, Vβ, Vδ, Jα, Jγ, Cα, Cγ, Dβ, and Dδ). (Thomas et al. Abstract, [0011], [0015], [0024], [0032], [0035], [0040], [0045], [0050], [0061], [0089], and [0098]; and FIGS. 1A, 4, 5B). Finn et al. teaches “and Cα (P3) or Cβ (P4) reverse primers.” (Finn et al. [0158]). This is interpreted as encoding a 5’ portion of a Cα.
Regarding claim 12, Thomas et al. teaches cloning of various segments (e.g., Vα, Vγ, Vβ, Vδ, Jα, Jγ, Cα, Cγ, Dβ, and Dδ). (Thomas et al. Abstract, [0011], [0015], [0024], [0032], [0035], [0040], [0045], [0050], [0061], [0089], and [0098]; and FIGS. 1A, 4, 5B).
Regarding claim 13, Thomas et al. teaches cloning of various segments (e.g., Vα, Vγ, Vβ, Vδ, Jα, Jγ, Cα, Cγ, Dβ, and Dδ). (Thomas et al. Abstract, [0011], [0015], [0024], [0032], [0035], [0040], [0045], [0050], [0061], [0089], and [0098]; and FIGS. 1A, 4, 5B).
Regarding claim 14, Finn et al. teaches Jβ (Finn et al. [0162]).
Regarding claim 15, Finn et al. teaches Cβ (Finn et al. [0162]).
Regarding claim 16, Thomas et al. teaches cloning of various segments (e.g., Vα, Vγ, Vβ, Vδ, Jα, Jγ, Cα, Cγ, Dβ, and Dδ). (Thomas et al. Abstract, [0011], [0015], [0024], [0032], [0035], [0040], [0045], [0050], [0061], [0089], and [0098]; and FIGS. 1A, 4, 5B). Finn et al. teaches Jβ (Finn et al. [0162]). Finn et al. teaches Cβ (Finn et al. [0162]).
Regarding claims 17-19, Thomas et al. teaches “Next, the first-step PCR products
were used as a mega primer with the appropriate clone from the library (e.g., TRGV9/TRDV2 with an irrelevant CDR3) as a template for the second-step overlap extension PCR. By using this substitution method, different yδ TCRs with matched CDR3s from the human single cell PCR products were successfully cloned.” (Thomas et al. [0106]). This is interpreted as Thomas et al. having a first amplification product comprising an adapter sequence added to an amplified template sequence of cDNA via a second round amplification of said amplifying. This interpretation is because PCR is well known as containing an adapter sequence when amplicon sequencing, or in this case, cloning of products. It is also suggested that it can be done multiple times, indicating a second product.
Regarding claim 20, Thomas et al. teaches cloning of various segments (e.g., Vα, Vγ, Vβ, Vδ, Jα, Jγ, Cα, Cγ, Dβ, and Dδ). (Thomas et al. Abstract, [0011], [0015], [0024], [0032], [0035], [0040], [0045], [0050], [0061], [0089], and [0098]; and FIGS. 1A, 4, 5B).
Regarding claims 21 and 22, Finn et al. teaches these above in the rejection over claim 2.
Regarding claim 23, Finn et al. teaches a full length α and β constant region respectively. (Finn et al. [0042]).
Regarding claim 24, Finn et al. teaches an IRES (Finn et al. [0098]).
Regarding claim 25, Thomas et al. teaches sorting intro separate locations. (Thomas et al. claim 3).
Regarding claim 26, Thomas et al. teaches reverse transcription reaction to obtain cDNA. (Thomas et al. [0084]).
Regarding claim 27, Thomas et al. teaches cloning for assembly. (Thomas et al. [0087]). This is inherently seamless cloning.
Regarding claim 28, Thomas et al. teaches “The PCR products were examined by agarose gel electrophoresis before sequencing (FIG. lB).” (Thomas et al. [0095]). This is interpreted as assembling of the nucleic acid that was obtained without performing sequencing.
Regarding claim 29, Thomas et al. teaches a method without restriction endonuclease cleavage reaction (Thomas et al. [0097]).
CONCLUSION
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MORGAN TAYLOR LINDGREN BALTZELL whose telephone number is (571)270-3350. The examiner can normally be reached Monday-Friday 8:00am-5:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached on 5712705919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MORGAN TAYLOR LINDGREN BALTZEL/ Examiner, Art Unit 1636
/Anna Skibinsky/
Primary Examiner, AU 1635
Prosecution Insights