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 .
Status of Claims
Claims 3-16, 18-33, 37-98, are new.
Claims 1, 2, 9, 18, 21, 23, 28, 29, 33, 34, 39, 41 and 45 are amended.
Claims 1, 2, 9, 18, 21, 23, 24, 27-30, 33, 34, 36, 38, 39, 41, 45 and 46 are currently under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The U.S. effective filing date of all claims under examination is set at 08/27/2020 based on the provisional application GB2013477.1 (filed 08/27/2020).
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 02/24/2023, 06/30/2023, 06/30/2023, 06/30/2023, 10/09/2023, 11/16/2023, 01/22/2024, 02/02/2024, 03/11/2024, 07/09/2024, 08/21/2024, 10/14/2024, 02/21/2025, 02/25/2025, 08/04/2025, 08/22/2025 are being considered by the examiner.
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." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claims 2, 9, 18, 24, 30, 36, 38 and 46 are objected to because of the following informalities:
Claim 2 appears to have a typographical error. There should be a punctuation “;” after the phrase “L is a linker sequence” before the term “(f)”.
Claim 9 appears to have several typographical errors as listed below:-
In (g) (ii): there should be a comma “,” between CD3ζ and CD45.
In (g) (ii) and (iii): 4-1BB and 41BB are presented in these sections respectively. The abbreviations should be made consistent if they represent the same protein.
In (g) (iv): there is an extra “,” before the term “syk” that should be deleted; there is an extra “)” after the phrase “syk family tyrosine kinases” that should be deleted; there is a missing “,” before “CD2”; the word “and” between “CD5 and CD28” should be replaced with a “,”; there is an extra “,” after CD28; the symbol “ϒ” should replace the alphabet “y” in “Fcy RIII”; the symbol “ɛ“ should replace the alphabet “s” in “FcsRI”;
In (h) (iii): there is an unnecessary space in the abbreviation of the term “JAK 2” which should be changed to “JAK2”; there is an unnecessary space in the abbreviation of the term “JAK 3” which should be changed to “JAK3”; there is an extra term of “receptor” in the sentence which presently reads “an interleukin receptor (IL) receptor”. The first “receptor” should be deleted.
Claim 18 appears to have two typographical errors as listed below:-
Line (vi) should be “(v)”following from the previous line of (iv).
It appears that Applicant mean to recite “and/or” after (d) and before (e ).
Claim 24 appears to have a typographical error, “therefor” should be “thereof” in (b) (i). There are three occurrences of “therefor” in this line.
Claim 30 appears to have a typographical error, the punctuation “,” should be changed to “;”, and the term “or” should be added after (b) and before (c).
Claim 36 appears to have two typographical errors:-
In (d), the word “and” should replace the punctuation “,” between CD48 and CXCL11.
In (g), ”an antigen binding domain comprises” should be changed to “antigen binding domain comprising”.
Claim 38 appears to have two typographical errors:-
The hyphen after the word “autoimmune” is unnecessary
The punctuation “.” before the term “ALS” should be deleted.
Claim 46 appears to have a typographical error, a comma should be included before the word “wherein”.
Appropriate correction is required.
Claim Rejections - 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 2, 9, 23, 24, 27, 33, 34, 36, 38 and 39 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 is unclear whether the claim requires meeting just one of (a) through (g), or the limitation requires (a) through (e) and anyone of (f) or (g), when the phrase “and/or” is recited between (f) and (g) only. The presence of multiple interpretations renders the claim indefinite.
This verbiage is also present in claim 9 such that it is unclear which limitations of the claim components (a) through (h) are required when the phrase “and/or” is recited between (g) and (h) only. Thus, this claim carry the same multiple interpretation issue and is rejected here as well.
See Ex parte Miyazaki, 89 USPQ2d 1207 (BPAI 2008) ("[R]ather than requiring that the claims are insolubly ambiguous, we hold that if a claim is amenable to two or more plausible claim constructions, the USPTO is justified in requiring the applicant to more precisely define the metes and bounds of the claimed invention by holding the claim unpatentable under 35 U.S.C. §112, second paragraph, as indefinite.").
Claims 9 and 24 recite the term “preferably” and/or the phrase “more preferably”. Claim 9 and 33 also recite the term “particularly”. In addition, claim 36 recites the phrase “such as”. The metes-and-bounds of the claims are unclear because it is unclear how, or if, possible limitations following “preferably, “more preferably’, “particularly”, and “such as” limit the claims.
Claim 23 recites the phrase “production host cells”. It is unclear what this terminology or phrase refers to for the host cells as this is not a commonly encountered terminology to use the word “production” to describe “host cells” in the art.
Claim 38 is dependent on cancelled claim 32. Thus, it is unclear what method claim 38 is further limiting and so the scope of the claim is indefinite.
Claim 39 recites in (b) “the step of introducing into the cell”. There is lack of antecedent basis for “the step” as claim 39 depends on claim 1 which does not recite “a step” in the latter claim.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 2, 9, 18 and 36 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
In particular regards to claim 9, the claim is directed to (i) a genus of CAR antigen binding domains comprising VH CDRs and VL CDRs comprising recited SEQ ID NOs with 1-3 amino acid modifications, (ii) a genus of CAR antigen binding domains comprising a VH domain that has as little as 70% sequence identity to SEQ ID NO. 17 and a VL domain that has as little as 70% sequence identity to SEQ DI NO:18, (iii) a genus of CAR antigen binding domains comprising a VH domain that has as little as 70% sequence identity to SEQ ID NO. 26 and a VL domain that has as little as 70% sequence identity to SEQ ID NO. 27, and (iv) a genus of CAR antigen binding domains that have as little as 80% sequence identity to SEQ ID NO(s). 19, 88 or 28. In particular regards to claim 18, the claim is inclusive of the genus of CAR antigen binding domains that have as little as 80% sequence identity to SEQ ID NO(s). 19 or 88. Likewise, claim 36 is inclusive of the genus of CAR antigen binding domains that have as little as 80% sequence identity to SEQ ID NO(s). 19, 88 or 28.
However, the written description sets forth with full structural sequence of two species for the recited VH domains encompassed by the genera of claim 9 (SEQ ID NO. 17 for VH 3PB2 and SEQ ID NO. 26 for VH 3PF12 in Sequence Listing), two species for the recited VL domains encompassed by the genera of claim 9 (SEQ ID NO. 18 for VL 3PB2 and SEQ ID NO. 27 for VL B11 in Sequence Listing) and two species for the recited antigen binding domains of claims 36 and 18 (SEQ ID NO. 28 for scFv, SEQ ID NO. 88 for 3PB2 scFv and SEQ ID NO:19 for 3PB2 scFv with variant amino acids in residues 118 to 142 in Sequence Listing) from the instant application. In addition, from the WO2020044055A1 application that has been incorporated by reference to the instant specification (see Pg. 37 of instant specification), an additional four species for the VH domain as recited in SEQ ID NO(s): 54-57 (Pg. 32) were disclosed, an additional fifteen species for the VL domain as recited in SEQ ID NO(s): 58-72 (Pg. 32-34) were disclosed, and an additional fifteen species for the antigen binding domain as recited in SEQ ID NO(s): 34 and 73-86 (Pg. 34-36) were disclosed. The specification does not disclose, and the art does not teach, the genera as broadly encompassed in the claims. Therefore, a total of six VH domains, seventeen VL domains and seventeen antigen binding domains were disclosed in its entirety.
Claim 2 is also inclusive of a genus of safety switch polypeptides that have as little as 80% sequence identity to SEQ ID NO. 1, 92 or 93. Further claim 18 is also inclusive of a genus of safety switch polypeptide comprising as little as 80% identity to SEQ ID NO. 10, 94, or 95, a genus of leader sequence with as little as 80% sequence identity to SEQ ID NO. 66, a genus of CD8a hinge and transmembrane domain with as little as 80% sequence identity to SEQ ID NO. 68, a genus of CD28 co-stimulatory domain with as little as 80% sequence identity to SEQ ID NO. 71, a genus of CD3zeta signaling domain with as little as 80% sequence identity to SEQ ID NO. 72.
However, the written description only reasonably conveys in the Sequence Listing:-
Six species of safety switch polypeptides encompassed by the genera of claims 2 and 18 (SEQ ID NO(s). 1, 10 and 92-95 (Sequence listing);
Two species of leader sequence encompassed by the genus of claim 18 (SEQ ID NO(s). 66 and 75;
Two species of CD8a hinge and transmembrane encompassed by genus of claim 18 (SEQ ID NO. 68 and 70);
One species of CD28 co-stimulatory domain encompassed by genus of claim 18 (SEQ ID NO. 71); and
Two species of CD3zeta signaling domain encompassed by genus of claim 18 (SEQ ID NO. 72, 76).
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common to that genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.”
The inventions at issue in Lilly were DNA constructs per se, the holdings of that case is also applicable to claims such as those at issue here. Further, disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product. See Ariad, 598 F.3d at 1354-55 (“Regardless whether the asserted claims recite a compound, Ariad still must describe some way of performing the claimed methods... the specification must demonstrate that Ariad possessed the claimed methods by sufficiently disclosing molecules capable of reducing NF-kB activity so as to ‘satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of the invention that is claimed.’”) (internal citation omitted); see also Univ. of Rochester v. G.D. Searle& Co., Inc., 358 F.3d916,918 (Fed.Cir.2004) (applying the same analysis to assess written description for claims to a “method for selectively inhibiting” a particular enzyme by administering a functionally defined compound, i.e., a “non-steroidal compound that selectively inhibits activity” of the gene product for that enzyme).
In regard to claims to a product defined by function, without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 at1568 USPQ2d at 1406 (“definition by function…does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
The instant specification fails to provide sufficient descriptive information, such as definitive structural features that are common to the genera. That is, the specification provides neither a representative number of (i) CAR VH CDRs and VL CDRs, (ii) CAR VH domains, (iii) CAR VL domains and (iv) CAR antigen binding domains that encompass the genera of (i) CAR antigen binding domains comprising VH CDRs and VL CDRs comprising 1-3 amino acid modifications, (ii) CAR antigen binding domains comprising a VH domain that has as little as 70% sequence identity to SEQ ID NO. 17 and a VL domain that has as little as 70% sequence identity to SEQ DI NO:18, (iii) CAR antigen binding domains comprising a VH domain that has as little as 70% sequence identity to SEQ ID NO. 26 and a VL domain that has as little as 70% sequence identity to SEQ ID NO. 27, and (iv) CAR antigen binding domains that have as little as 80% sequence identity to SEQ ID NO(s). 19, 88 or 28, nor does it provide a description of structural features that are common to the genera so that one of skill in the art can ‘visualize or recognize’ the members of the genera. Likewise, the specification provides neither a representative number of safety switch polypeptides, leader sequences, CD8a hinge and transmembrane sequences, CD28 co-stimulatory domains and CD3zeta signaling domains that encompass the genera of safety switch polypeptides comprising as little as 80% identity to SEQ ID NO. 1, 10, 92-95, leader sequence with as little 80% sequence identity to SEQ ID NO. 66, CD8a hinge and transmembrane domain with as little 80% sequence identity to SEQ ID NO. 68, CD28 co-stimulatory domain with as little 80% sequence identity to SEQ ID NO. 71, and CD3zeta signaling domain with as little 80% sequence identity to SEQ ID NO. 72, nor does it provide a description of structural features that are common to the genera so that one of skill in the art can ‘visualize or recognize’ the members of the genera.
“[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
Further, in view of Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017) and the Office’s February 2018 memo clarifying written description guidance for claims drawn to antibodies, the 2008 Written Description Training Materials are outdated and should not be relied upon as reflecting the current state of law regarding 35 U.S.C. 112. Further, a “newly characterized antigen” test flouts basic legal principles of the written description requirement (Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017)). Adequate written description of a newly characterized antigen alone is not considered adequate written description of a claimed antibody to that newly characterized antigen. Where an antibody binds to an antigen tells one nothing about the structure of any other antibody. Also, see the Board’s decision in Appeal 2017-010877 (claims to “A monoclonal antibody that binds a conformational epitope formed by amino acids 42-66 of SEQ ID NO:1”).
The functional requirements of the claimed CAR antigen binding domains, for example, is the sort of wish list of properties which fails to satisfy the written description requirement because CAR antigen binding domains with those properties have not been adequately described. Centocor, 636 F.3d at 1352. The “claims merely recite a description of the problem to be solved while claiming all solutions to it and . . . cover any compound later actually invented and determined to fall within the claim’s functional boundaries—leaving it to the pharmaceutical industry to complete an unfinished invention.”Ariad Pharmaceuticals, Inc. v. EliLilly and Co.,598 F.3d 1336, 1353 (Fed. Cir. 2010).
Since the disclosure fails to describe common attributes or characteristics that adequately identify members of the genera, and because the genera are highly variant, the disclosure is insufficient to describe the genera. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genera as broadly claimed.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, even though Applicant may propose methods of screening for possible members of the genera, the skilled artisan cannot envision the detailed chemical structure of the encompassed genera, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolation. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. See Ariad, 94 USPQ2d at 1161; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Claim Rejections - 35 USC § 112(a)
Claim 29 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treatment of a disease such as inflammation, cellular and/or humoral transplant rejection, graft-versus-host disease (GvHD), autoimmune or allergic diseases by administering recited reagents, does not reasonably provide enablement for prevention of said diseases or just any disease by administering recited reagents. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claim 29, as written, include methods of preventing a disease in an individual predisposed to any disease. On Pg. 66, the instant specification discloses that preventing a disease or condition relates to the prophylactic use of the cells herein. In this respect, the cells may be administered to a subject who has not yet contracted or developed the disease or condition and/or who is not showing any symptoms of the disease or condition to prevent the disease or condition or to reduce or prevent development of at least one symptom associated with the disease or condition. However, the specification lacks guidance and or objective evidence with regards to prevention, for example by vaccination, of a population of subjects predisposed to inflammation, cellular and/or humoral transplant rejection, graft-versus-host disease (GvHD), autoimmune or allergic diseases. It is well known in the art that the prevention of a disease, in general, is highly unpredictable and applicant have not demonstrated, with any predictability, that the claimed cell expressing claimed polypeptides would predictably prevent the occurrence of any disease. Reasonable guidance with respect to preventing any disease relies on quantitative analysis from defined populations; some of which have been successfully pre-screened and are predisposed to particular types of disease. This type of data might be derived from widespread genetic analysis, cancer clusters, family histories, or randomized controlled trials. For example, Byers, T. (CA Cancer Journal for Clinicians, Vol. 49, No. 6, Nov/Dec. 1999) teaches that randomized controlled trials are commonly regarded as the definitive study for proving causality (1st col., p.358), and that in controlled trials the random assignment of subjects to the intervention eliminates the problems of dietary recalls and controls the effects of both known and unknown confounding factors. Further, Byers suggests that chemo-preventative trials be designed “long-term” such that testing occurs over many years (2nd col., p. 359). Further, the essential element towards the validation of any preventive therapeutic is the ability to test the drug on subjects monitored in advance of clinical cancer. This would require monitoring a large population with the claimed agents and linking such results with subsequent histological confirmation of the presence or absence of disease. Thus, while the specification is enabling for treating a disease in a patient who has been diagnosed with inflammation, cellular and/or humoral transplant rejection, graft-versus-host disease (GvHD), autoimmune or allergic diseases by administering recited reagents, the specification lacks reasonable guidance, predictability, and objective evidence that enables the prevention of inflammation, cellular and/or humoral transplant rejection, graft-versus-host disease (GvHD), autoimmune or allergic diseases by administering recited reagents.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 21, 23, 28, 29, 39, 41 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Jäckel et al. (EP3478710B1 Date Published 2019-05-08) in view of DiStasi et al. (N Engl J Med 1673-1683, 2011) and Winiarska et al. (Mol Med Rep. 2017 Sep;16(3):3041-3048).
Jäckel et al. teaches an expression cassette adapted to generate one unified mRNA encoding the fusion protein of CAR-P2A-FOXP3 suitable for providing Treg cells with suppressor activity to suppress an immune response (Paragraphs [0013], [0015] and [0016] and Fig. 5). Jäckel et al. also teaches Treg cells that express CAR-A*02 also express FOXP3 constitutively by introduction of an expression cassette encoding human FOXP3 concurrent with introducing the nucleic acid sequence encoding the CAR-A*02 into a Treg cell and can also express a caspase-9 dimerizer system (Paragraph [0015]). DiStasi et al. teaches that the caspase-9 dimerizer system is an inducible T-cell “safety switch” that is based on the fusion of human caspase 9 to a modified human FK-binding protein, allowing conditional dimerization which when exposed to a synthetic dimerizing drug, the inducible caspase 9 (iCasp9) becomes activated and leads to the rapid death of cells expressing this construct.
Jäckel et al. teaches the process for making human Treg cells having suppressor activity in the presence of HLA-A*02 positive solid tissue, comprising the steps of isolating from a blood sample CD4+CD25+CD127low human Treg cells to produce isolated Treg cells, and introducing a nucleic acid sequence encoding and expressing the FOXP3 and CAR fusion protein into the isolated Treg cells to produce Treg cells expressing the fusion protein (claim 16), wherein the nucleic acid sequence is comprised in a retroviral vector that is packaged in a retroviral particle and is introduced into the isolated Treg cells by transduction (Paragraph [0019] and claims 18 19). They teach that the CAR-A*02 expressed in a human Treg cell, and the human Treg cell expressing the CAR-A*02, are pharmaceutical compounds for the treatment of HvG (host versus graft) disease. They also teach a method of treatment of HvG disease, comprising the administration of Treg cells expressing the fusion protein CAR-A*02 to the patient (Paragraph [0005]).
Jäckel et al. does not specifically teach the safety switch nucleotide sequence, the FOXP3 nucleotide sequence and the CAR nucleotide sequence are operably linked to an SFFV promoter. They also do not specifically teach a method of enhancing the expression of FOXP3 from a nucleic acid molecule encoding a CAR, a safety switch and FOXP3 in a cell, wherein the method comprises operably linking the safety switch nucleotide sequence, the FOXP3 nucleotide sequence and the CAR nucleotide sequence to a SFFV promoter. However, these deficiencies are made up in the teachings of Winiarska et al.
Winiarska et al. teaches that lentiviral vectors were generated that contained various promoters, including cytomegalovirus (CMV), elongation factor‑1 alpha (EF1α) and spleen focus‑forming virus (SFFV) (Abstract and Fig. 6). Winiarska et al. also teaches that SFFV promoter resulted in a higher level of transgene expression compared with CMV or EF1α promoters to drive the expression of the selected genes-of-interest (Abstract & Fig. 4).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of making an expression construct, a vector and a cell comprising a nucleotide encoding a safety switch polypeptide, a nucleotide encoding a FOXP3, and a nucleotide encoding a CAR as taught by Jäckel et al. to suppress an immune response and wherein the said nucleotide sequences are operably linked to the SSFV promoter as taught by Winiarska et al. because Winiarska et al. teaches that SFFV promoter enhanced the levels of transgene expressions compared to two other studied promoters (Abstract). This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
With regards to making components of the expression construct 5’ to 3’ in the order recited by instant claim 1, a person having ordinary skill in the art would have made such a construct in any particular order since the sequences were known and the techniques involved in cloning said sequences into a vector in any order and then introducing the vector into a cell were well known in the art.
With regards to claim 29, it would have been obvious before the filing of the instant application to one of ordinary skill in this art to perform said combined method where a subject is administered a Treg cell obtained from the subject comprising the expression construct for treating HvG disease because Jäckel et al. teaches that the expressed FOXP3 is cleaved off and can translocate into the nucleus (Paragraph [0064]) and the administration of Treg cells expressing a CAR-A*02 into mice completely prevented the rejection of allogeneic target cells in mouse models (Paragraph [0063]).
Taken together, the combination of art above clearly renders the claimed inventions above as a whole prima facie obvious.
Claim Rejections - 35 USC § 103 (second)
Claims 1, 2, 9, 18, 21, 23, 24, 27, 28, 29, 30, 39, 41, 45 and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Jäckel et al. (EP3478710B1 Date Published 2019-05-08) in view of Pulé et al. (US20150093401A1 Date Published 2015-04-02), Winiarska et al. (Mol Med Rep. 2017 Sep;16(3):3041-3048), Liu et al. (Sci Rep 7, 2193 (2017) and Watkins et al. (Tissue Antigens 55(3): 219-228, 2000).
Jäckel et al. teaches a CAR fusion protein for suppressing immune response. They teach an expression cassette adapted to generate one unified mRNA encoding the fusion protein of CAR-P2A-FOXP3 for suppressing immune response when expressed in Treg cells (Paragraphs [0013], [0015] and [0016] and Fig. 5). Jäckel et al. also teaches Treg cells that express CAR-A*02 also express FOXP3 constitutively by introduction of an expression cassette encoding human FOXP3 concurrent with introducing the nucleic acid sequence encoding the CAR-A*02 into a Treg cell (Paragraph [0015]). They teach that CAR-A*02 is an HLA-A2 CAR (Paragraph [0050]) and the leader sequence is SEQ ID NO: 24. The SEQ ID NO: 24 of Jäckel et al. has 100% identity match to instant SEQ ID NO. 66 recited in instant claim 18.
Jäckel et al. teaches the expression of FOXP3 with the fusion protein CAR-A*02 can be by expression of a fusion of P2A with C-terminally fused FOXP3 in one unified fusion protein, e.g. directly fused to the C-terminus of CAR-A*02. Such a fusion encoded by one expression cassette adapted to generate one unified mRNA encoding the fusion protein of CAR-P2A-FOXP3, would yield free FOXP3 by its hydrolysis from the P2A domain. They teach that the P2A sequence is arranged such that following expression, FOXP3 is cleaved off and can translocate into the nucleus (Paragraph [0064]). Jäckel et al. teaches the fusion of P2A-FOXP3 has a sequence as set forth in SEQ ID NO: 22 (Paragraphs [0016] and [0022]). The amino acid residue from residues 23 to 452 of SEQ ID NO: 22 taught by Jäckel et al. has 100% identity to instant SEQ ID NO. 2 (FOXP3 polypeptide amino acid sequence).
Jäckel et al. teaches the CAR-A*02 contains a scFv domain that is specific for the human HLA-A*02 that provides Treg cells with suppressor activity for an MHC class I (Paragraphs [0013] and [0014]), which means the CAR is not directed against MHC class II. Jäckel et al. also teaches CAR-A*02 is a fusion protein comprising a scFv, a CD8 hinge, an intracellular CD8 transmembrane domain or a hCD28 transmembrane domain, an hCD28 signaling domain and an intracellular hCD3zeta signaling domain (Paragraph [0017]). They teach the CD8 hinge and CD8 transmembrane domain has an amino acid sequence of SEQ ID NO: 13, which is an exact match to instant SEQ ID NO. 68 for the CD8a hinge and transmembrane domain sequence in instant claim 18 (c). They also teach the CD28 signaling domain has an amino acid sequence of SEQ ID NO: 14 (100% match to instant SEQ ID NO. 71), and the CD3 signaling domain has an amino acid sequence of SEQ ID NO: 15 (100% match to instant SEQ ID NO. 72) (Paragraph [0017]).
Jäckel et al. does not specifically teach the safety switch polypeptide comprises a suicide moiety which is recognized by an antibody, and wherein binding of the antibody to the safety switch polypeptide, when expressed on the surface of a cell, causes the cell to be eliminated, optionally wherein the suicide moiety is a CD20 epitope which is recognized by the antibody Rituximab. They also do not specifically teach the safety switch polypeptide comprises a sequence having the formula: R1-L-R2-St wherein R1 and R2 are Rituximab-binding epitopes; St is a stalk sequence which, when the polypeptide is expressed at the surface of a cell, causes the R1 and R2 epitopes to be projected from the cell surface; and L is a linker sequence, or wherein the safety switch polypeptide is the polypeptide RQR8 having the sequence of SEQ ID NO. 1. They do not specifically teach the safety switch nucleotide sequence, the FOXP3 nucleotide sequence and the CAR nucleotide sequence are operably linked to an SFFV promoter. They further do not specifically teach a nucleotide sequence encoding a T2A cleavage sequence. They also do not specifically teach a method of increasing the sensitivity of a cell expressing a safety switch polypeptide comprising a suicide moiety of at least one CD20 epitope recognized by Rituximab, to Rituximab, comprising introducing into said cell a nucleic acid molecule comprising a nucleotide sequence encoding said safety switch polypeptide wherein said nucleotide sequence is operably linked to a SFFV promoter.
Jäckel et al. also does not specifically teach the CAR comprises an antigen binding domain which comprises VH CDR1, 2 and 3 sequences as set forth in SEQ ID NOs. 11, 12 and 13 respectively and VL CDR1, 2 and 3 sequences as set forth in SEQ ID NOs. 14, 15, 16 respectively; or the CAR comprises an antigen binding domain which comprises a VH domain comprising the sequence as set forth in SEQ ID NO. 17, or a sequence having at least 70% sequence identity thereto, and a VL domain comprising the sequence as set forth in SEQ ID NO. 18, or a sequence having at least 70% sequence identity thereto; or the CAR comprises an antigen binding domain which comprises the sequence as set forth in SEQ ID NO. 88 or a sequence having at least 80% sequence identity thereto.
However, these deficiencies are remedied by the teachings of Pulé et al, Winiarska et al., Liu et al. and Watkins et al.
Pulé et al. teaches a polypeptide having the formula: St-R1-S1-Q-S2-R2 wherein St is a stalk sequence which, when the polypeptide is expressed at the surface of a target cell, causes the R and Q epitopes to be projected from the cell surface; R1 and R2 are a Rituximab-binding epitopes; S1 and S2 are optional spacer sequences, which may be the same or different; and Q is a QBEnd1O-binding epitope (Abstract). Pulé et al. also teaches a nucleic acid sequence encoding such a polypeptide and uses thereof in adoptive cell transfer or ACT (Abstract). They teach the said polypeptide can be fused to a chimeric antigen receptor (CAR) (claims 8 and 9). They also teach that the said polypeptide comprises the sequence shown as SEQ ID No. 4 that is able to bind Rituximab and when expressed on the surface of a cell, induces complement-mediated killing of the cell in the presence of Rituximab (claim 7). The SEQ ID No. 4 taught by Pulé et al. has 99.5 identity to instant SEQ ID NO. 1 recited as the safety switch polypeptide that is RQR8 in instant claim 2 (f) (see alignment below where instant SEQ ID NO. 1 is present as the top sequence).
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Pulé et al. teaches in Paragraph [0121] that a polypeptide comprising a signal peptide and the 136 amino acid sequence of SEQ ID NO. 4 would be a 157 amino acid sequence as set forth in SEQ ID No. 19). This SEQ ID NO. 19 of Pulé et al. has a 100% match to instant claim 10 SEQ ID NO. 10. They also teach that cells expressing the polypeptide and CAR fusion may co-express the polypeptide and the CAR at the cell surface (Paragraph [0054]). They further teach that the cell may be a T cell, such as a cytotoxic T lymphocyte (CTL) (Paragraph [0145]) and that T cell populations which are suitable for ACT include: bulk peripheral blood mononuclear cells (PBMCs), CD8+ cells (for example, CD4-depleted PBMCs); PBMCs that are selectively depleted of T-regulatory cells (Tregs); isolated central memory (Tcm) cells; EBV-specific CTLs; and tri-virus-specific CTLs (Paragraph [0147]). Pulé et al. also teaches the RQR8 construct at a length of 136 amino acids long is a much more manageable size than the full length CD34 marker gene with the added advantage of comprising a suicide gene element with lytic sensitivity at least equal to that demonstrated by full-length CD20 (Paragraph (0124]) and with a binding of Rituximab that is 3.4 fold increased relative to native CD20 (Paragraph [0189]).
Winiarska et al. teaches that lentiviral vectors were generated that contained various promoters, including cytomegalovirus (CMV), elongation factor‑1 alpha (EF1α) and spleen focus‑forming virus (SFFV) (Abstract and Fig. 6). Winiarska et al. also teaches that SFFV promoter resulted in a higher level of transgene expression compared with CMV or EF1α promoters to drive the expression of the selected genes-of-interest (Abstract & Fig. 4).
Liu et al teaches that 2A sequences include the F2A (foot-and-mouth disease virus), E2A (equine rhinitis A virus), P2A (porcine teschovirus-1 2A), and T2A (thosea asigna virus 2A) sequences (Introduction).
Watkins et al. teaches in Table 3, the amino acid sequences of the VH and VL genes encoding the anti-HLA-A2 antibody 3PB2. The VHCDRs and VLCDRs are clearly denoted in the Table, along with the FR regions. Alignment of the 3PB2 VH and VL sequences show that they are an exact match to instant VH SEQ ID NO. 17 and instant VH SEQ ID NO. 18 respectively. The CDRs also match perfectly to instant SEQ ID NO(s). 11, 12 and 13 for the VHCDRs and instant SEQ ID NO(s). 14, 15 and 16 for the VLCDRs. The combined sequence of 3PB2 VH and 3PB2VL taught by Watkins et al. produce a sequence which is 100% identical to instant SEQ ID NO. 88 set forth for the instant CAR antigen binding domain.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making an expression construct for suppressing immune response of Jäckel et al. comprising expressing in immune cells of Jäckel et al. a nucleotide encoding a safety switch polypeptide comprising the components of R1, S1/S2, R2 and St as taught by Pulé et al. (same as RQR8 and SEQ ID NO: 1 recited by instant claim 2), a nucleotide encoding a FOXP3, a nucleotide encoding a CAR, and the said nucleotide sequences are separated by P2A sequences that encode self-cleavage sequences as taught by Jäckel et al., and include the TA2 sequence as taught by Liu et al., while substituting the antigen binding domain of the CAR of Jäckel et al. for those taught by Watkins et al., and wherein the said nucleotide sequences are operably linked to the SSFV promoter as taught by Winiarska et al. because Pulé et al. teaches that the safety switch construct of Pulé et al. (same as RQR8 and SEQ ID NO: 1 recited by instant claim 2) has the advantage of comprising a suicide gene element with lytic sensitivity at least equal to that demonstrated by full-length CD20 (Paragraph [0124]), Liu et al. teaches that T2A and P2A peptides have the highest self-cleaving efficiencies (Pg. 2 Paragraph, first), Watkins et al. teaches the 3PB2 anti- HLA-specific alloantibodies isolated from an alloimmunised human patient can specifically recognize native antigen (Abstract and Pg. 220 Column, first, Paragraph, second), and Winiarska et al. teaches that SFFV promoter enhanced the levels of transgene expressions compared to two other studied promoters (Abstract). This is an example of (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
With regards to making components of the expression construct 5’ to 3’ in the order recited by instant claim 1, a person having ordinary skill in the art would have made such a construct in any particular order since the sequences were known and the techniques involved in cloning said sequences into a vector in any order and then introducing the vector into a cell were well known in the art.
With regards to claim 2 where the safety switch polypeptide comprises a sequence having the formula: R1-L-R2-St, since Pulé et al. teaches S1 and S2 are spacer sequences that may have a combined length of at least about 10 amino acids (Paragraph [0042]), these are interpreted to be equivalent to the instant claim’s linkers. Further, even though Pulé et al. does not specifically teach this order of the formula for the safety switch polypeptide, a person having ordinary skill in the art would have been able to make such a construct in this particular order since the sequences are known and the techniques involved in cloning said sequences into said order is well known in the art. Therefore, the order of the first, second and third nucleotide sequences in an expression construct would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Further, it would have been obvious before the filing of the instant application to one of ordinary skill in this art to perform said combined method where a subject is administered a Treg cell comprising the expression construct for treating HvG disease because Jäckel et al. teaches that the expressed FOXP3 is cleaved off and can translocate into the nucleus (Paragraph [0064]) and the administration of Treg cells expressing a CAR-A*02 into mice completely prevented the rejection of allogeneic target cells in mouse models (Paragraph [0063]).
Taken together, the combination of art above clearly renders the claimed inventions above as a whole prima facie obvious.
Claim Rejections - 35 USC § 103 (third)
Claims 1, 2, 9, 18, 21, 23, 24, 27, 28, 29, 30, 33, 34, 36, 39, 41, 45 and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Jäckel et al. (EP3478710B1 Date Published 2019-05-08), Pulé et al (US20150093401A1 Date Published 2015-04-02), Winiarska et al. (Mol Med Rep. 2017 Sep;16(3):3041-3048), Liu et al. Sci Rep 7, 2193 (2017) and Watkins et al. (Tissue Antigens 55(3): 219-228, 2000) as applied to claims 1, 2, 9, 18, 21, 23, 24, 27, 28, 29, 30, 39, 41, 45 and 46 above and further in view of Boardman et al. (Am J Transplant 2017 Apr;17(4):931-943).
The combined teachings of Jäckel et al., Pulé et al., Winiarska et al., Liu et al. and Watkins et al. render obvious instant claims 1, 2, 9, 18, 21, 23, 24, 27, 28, 29, 30, 39, 41, 45 and 46 as discussed above.
Jäckel et al., Pulé et al., Winiarska et al., Liu et al. and Watkins et al. do not teach a method of inducing tolerance to a transplant which comprises the step of administering to a subject a Treg cell, comprising the expression construct nucleic acid molecule of claim 1. However, these deficiencies are remedied by Boardman et al.
Boardman et al. teaches the engineering of HLA-A2-specific CARs to redirect human Tregs toward donor-MHC class I molecules, which are ubiquitously expressed in allografts, with the aim of promoting organ transplant tolerance (Abstract and Pg. 932 Column, second, Lines 1-3). They teach that mice transplanted with human skin graft and injected with CAR Tregs were protected from GvHD (graft versus host disease) throughout the experiment (Pg. 937 Column, second, Paragraph, first).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making and using an expression construct as taught by Pulé et al., Jäckel et al., Liu et al., Watkins et al., and Winiarska et al. for generation of Treg cells used in a method of inducing tolerance to a transplant or preventing GvHD as taught by Boardman et al. because Boardman et al. teaches that CAR technology can potentially generate donor antigen-specific Tregs that suppress alloimmune responses in the pursuit of transplant tolerance in solid organ transplantation (Boardman et al. Pg. 941 Column, first, Paragraph, first, conclusion). This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
With regards to claim 36, it would have been obvious to perform the combined method of using the CAR comprising an antigen binding domain comprising the 3PB2 anti-HLA A2 VH and VL domains as taught by Watkins et al. to the method of inducing tolerance to a transplant or protection from GvHD as taught by Boardman et al because this is substituting one anti-HLA A2 specific CAR of Boardman et al. for another anti-HLA A2 specific CAR of Watkins et al. (which is 100% identical to instant SEQ ID NO. 88 recited in claims 9, 18 and 36) to arrive at expected results of managing said diseases taught by Boardman et al. "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.). See also In re Leshin, 277 F.2d 197, 125 USPQ 416 (CCPA 1960) (selection of a known plastic to make a container of a type made of plastics prior to the invention was held to be obvious)
Taken all together, the combination of art above clearly renders the claimed inventions above as a whole prima facie obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fe