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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 1-22-26 has been entered.
Applicant's arguments filed 1-22-26 have been fully considered but they are not persuasive.
Claims 1-83, 85, 87, 89, 97-102, 108-121 have been canceled. Claims 122-126 have been added. Claims 84, 86, 88, 90-96, 103-107, 122-126 are pending.
Election/Restrictions
Applicants elected Group I, claims 84-102, in the response filed 6-26-20. Claims 103-107 remain withdrawn.
The restriction and species election may have to be redone once the claims have been clarified.
Claims 84, 86, 88, 90-96, 122-126 are under consideration.
Claim Objections
The concept of an engineered TCR-presenting cell in claim 84 is confusing and unclear because all T-cells express TCRs, so calling them TCR-presenting cells is scientifically, logically, and scientifically confusing. It’s just a T-cell. The phrase ---a genetically modified isolated mammalian T-cell--- would be clear.
If applicants are attempting to have claim 84 encompass T-cells as well as cells that are not T-cells, then much clarification is required. For example, if applicants are attempting to have claim 84 encompass any generic isolated mammalian cell that has all endogenous TCR genes inactivated and expresses exogenous TCRs, then those genetic modifications are not clearly set forth. The use of jargon like “eTPC-t” and “eTPC” are meaningless without clearly setting forth the genetic modification in the isolated mammalian cells.
If expression of an exogenous TCR in the generic mammalian cell imparts some function to the cell, then that is missing from claim 84. The use of jargon like “eTPC-t” and “eTPC” are meaningless without clearly setting forth the function of the isolated mammalian cells.
The “t” in the abbreviation “eTPC-t” in claim 84 still does not make sense because the letters do not correspond with the letters in “engineered T-cell receptor-presenting cells”.
The phrase “eTPC-t” in line 2 of claim 84 still does not match the term “eTPC” in line 4 of claim 84.
It is unclear how the T-cell in claim 84 is “engineered” because it does not clearly set forth the structure of the genetic modification. The phrase “has been engineered such that endogenous surface expression of the HLA class I, HLA class II, CD1, MR1 or aAM has been inactivated” does not necessarily indicate a genetic modification because the proteins can be inactivated by binding other proteins to them or by chemical means. If the genetic modification is the lack of endogenous HLA expression, then the claim should clearly state the genetically modified T-cell has a genome comprising an inactivated HLA gene.
The “a” and the “X” in the abbreviation “aAPX” do not make sense because there is only one word that starts with the letter A and there are no words that start with an X.
The meaning of the term MR1 in claim 84 cannot be determined.
The meaning of analyte antigenic molecule (aAM) in claim 84 cannot be determined. If it is just an antigen, then just say antigen. If “analyte” somehow further limits the structure/function of the antigen, then much clarification is required.
The structure/function of the T-cell lacking endogenous expression of a endogenous surface expression of the HLA class I, HLA class II, CD1, MR1 and/or an “analyte” antigen that “has been engineered such that endogenous surface expression of the HLA class I, HLA class II, CD1, MR1 or aAM has been inactivated” in claim 84 cannot be determined for reasons set forth above. If the T-cells are genetically modified to cause the lack of expression, then the claim should simply state ---an isolated mammalian T-cell whose genome comprises an inactivated endogenous HLA class I, HLA class II, CD1, MR1, or antigen gene, wherein the T-cell lacks surface expression of the HLA class I, HLA class II, CD1, MR1, or antigen ---.
The phrase “lacks endogenous expression of TCR chains alpha, beta, delta, and gamma, or has been engineered to inactivate endogenous expression” in claim 84 does not make sense grammatically, logically, legally, or scientifically. If the T-cells are genetically modified to cause the lack of expression of TCR chains alpha, beta, delta, and gamma, then the claim should simply state ---an isolated mammalian T-cell whose genome comprises inactivated endogenous TCR alpha, beta, delta, and gamma chain genes, wherein the T-cell lacks expression of the TCR alpha, beta, delta, and gamma chains ---.
The phrase “endogenously or exogenously” in the phrase “expresses endogenously or exogenously CD3γ, CD3d,…” in claim 84 is redundant because all proteins must be expressed endogenously or exogenously. Delete “endogenously or exogenously”.
The phrase “further comprises two single target sites for insertion of an exogenous nucleic acid encoding a TCR chain, wherein each target site is respectively a synthetic or native genomic receiver site for integration” in claim 84 is redundant because any two sequences in the genome of a T-cell can be used as homology arms for inserting exogenous DNA using a homology vector. Any sequence in the genome can be used for recombinase-mediated recombination or site directed homologous recombination. There is nothing in the phrase that further limits the structure or function of the target sites for the homology arms of a homology vector.
Claim 84 on pg 3, lines 4-11, in the response filed 1-22-26 never clearly sets forth that an exogenous sequence encoding a TCR alpha, beta, delta, or gamma chain has been inserted into the genome of the T-cell. Just saying the genome of the T-cell has target sites capable of receiving a homology vector comprising an exogenous sequence encoding a TCR alpha, beta, delta, or gamma chain is meaningless for reasons set forth in the paragraph above.
The metes and bounds of when exogenous sequences encoding a TCR alpha, beta, delta, or gamma chains are “a single complementary pair” in line 10 on pg 3 of claim 84 cannot be determined.
The metes and bounds of a “genetic receiver” that is a synthetic construct for “recombinase-mediated cassette exchange”, a synthetic construct for “site directed homologous recombination”, or a “native target site” in claim 84 cannot be determined. Again, these three categories of “genetic receivers” do not further limit the genome of the T-cells because any part of the genome of the T-cell can be used as homology arms for a homology vector, recombinase-mediated recombination, or site directed homologous recombination.
If the “genetic donor vector” is the second part of the system, then the T-cells should be item A) and the vector should be item B). Just say ---B) an isolated vector--- and clearly set forth the structure/function of the vector, e.g. ---comprising a nucleic acid sequence encoding a TCR alpha, beta, delta or gamma chain---.
The metes and bounds of when exogenous sequences encoding analyte TCR chains are “a single complementary pair” in line 21 on pg 3 of claim 84 cannot be determined.
The meaning of “wherein the one or more ORFs encoded by the [vector] recombine with the first genomic receiver site when introduced into the eTPC, and integrates” in line 23 on pg 3 of claim 84 cannot be determined. This appears as though applicants attempting to embed product-by-process language into the vector within item B) of the system of claim 84. Specifically, it appears as though applicants are attempting to say the exogenous sequence in the vector has “recombined” and “integrated”.
If applicants are attempting to add product-by-process language into item B) of claim 84, this is ill-advised because of the numerous issues with what is already a bulky and confusing claim.
If applicants are simply attempting to set forth a capability of the vector, then just say that e.g. ---wherein the nucleic acid sequence encoding a TCR alpha, beta, delta or gamma chain encoded by the vector is capable of integrating into the genome of the isolated mammalian T-cell---.
If applicants are attempting to say the genome of the T-cell already has the exogenous sequences, then just say that, e.g. an isolated mammalian T-cell whose genome comprises inactivated TCR alpha, beta, delta, and gamma genes and exogenous nucleic acid sequences encoding exogenous TCR alpha, beta, delta, and gamma chains, wherein the T-cell does not express endogenous TCR alpha, beta, delta, or gamma chains and DOES express the exogenous TCR alpha, beta, delta, and gamma chains---.
The remainder of claim 84 still has numerous clarity issues at the bottom of pg 3 and throughout pg 4.
For example, the limitations regarding CD3 on pg 4, lines 4-9, should be with the CD3 language on pg 2, last three lines. The limitations regarding the structure of the T-cells on pg 4, lines 10-20, should be with the T-cells in item A) on pg 2 of claim 84.
If there are only two components to the “system” of claim 84, i.e. A) isolated mammalian T-cells; and B) a vector, then claim 84 is more aptly a composition claim, e.g. ---A composition comprising: A) isolated mammalian T-cells; and B) a vector---.
If the vector has already been integrated into the genome of the T-cells, then the “system” is actually just isolated mammalian T-cells, which should be reflected in the preamble of claim 84, e.g. ---An isolated mammalian T-cell.
Response to comments
Applicants’ comments on pg 11-14 are noted but do not address these issues.
Claim Rejections - 35 USC § 112
Indefiniteness
Claims 84, 86, 88, 90-96, 103-107 remain and claims 122-126 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.
Pending rejections
A) The structure and function of the engineered mammalian TCR-presenting cells in claim 84 cannot be determined. The concept of an engineered TCR-presenting cell in claim 84 is confusing and unclear because all T-cells express TCRs, so calling them TCR-presenting cells is scientifically, logically, and scientifically confusing. It’s just a T-cell. The phrase ---a genetically modified isolated mammalian T-cell--- would be clear. If applicants are attempting to have claim 84 encompass T-cells as well as cells that are not T-cells, then much clarification is required. For example, if applicants are attempting to have claim 84 encompass any generic isolated mammalian cell that has all endogenous TCR genes inactivated and expresses exogenous TCRs, then those genetic modifications are not clearly set forth. The use of jargon like “eTPC-t” and “eTPC” are meaningless without clearly setting forth the genetic modification in the isolated mammalian cells. If expression of an exogenous TCR in the generic mammalian cell imparts some function to the cell, then that is missing from claim 84. The use of jargon like “eTPC-t” and “eTPC” are meaningless without clearly setting forth the function of the isolated mammalian cells. The “t” in the abbreviation “eTPC-t” in claim 84 still does not make sense because the letters do not correspond with the letters in “engineered T-cell receptor-presenting cells”. The phrase “eTPC-t” in line 2 of claim 84 still does not match the term “eTPC” in line 4 of claim 84. It is unclear how the T-cell in claim 84 is “engineered” because it does not clearly set forth the structure of the genetic modification. The phrase “has been engineered such that endogenous surface expression of the HLA class I, HLA class II, CD1, MR1 or aAM has been inactivated” does not necessarily indicate a genetic modification because the proteins can be inactivated by binding other proteins to them or by chemical means. If the genetic modification is the lack of endogenous HLA expression, then the claim should clearly state the genetically modified T-cell has a genome comprising an inactivated HLA gene. The meaning of analyte antigenic molecule (aAM) in claim 84 cannot be determined. If it is just an antigen, then just say antigen. If “analyte” somehow further limits the structure/function of the antigen, then much clarification is required. The structure/function of the T-cell lacking endogenous expression of a endogenous surface expression of the HLA class I, HLA class II, CD1, MR1 and/or an “analyte” antigen that “has been engineered such that endogenous surface expression of the HLA class I, HLA class II, CD1, MR1 or aAM has been inactivated” in claim 84 cannot be determined for reasons set forth above. If the T-cells are genetically modified to cause the lack of expression, then the claim should simply state ---an isolated mammalian T-cell whose genome comprises an inactivated endogenous HLA class I, HLA class II, CD1, MR1, or antigen gene, wherein the T-cell lacks surface expression of the HLA class I, HLA class II, CD1, MR1, or antigen ---. The phrase “lacks endogenous expression of TCR chains alpha, beta, delta, and gamma, or has been engineered to inactivate endogenous expression” in claim 84 does not make sense grammatically, logically, legally, or scientifically. If the T-cells are genetically modified to cause the lack of expression of TCR chains alpha, beta, delta, and gamma, then the claim should simply state ---an isolated mammalian T-cell whose genome comprises inactivated endogenous TCR alpha, beta, delta, and gamma chain genes, wherein the T-cell lacks expression of the TCR alpha, beta, delta, and gamma chains ---. The phrase “endogenously or exogenously” in the phrase “expresses endogenously or exogenously CD3γ, CD3d,…” in claim 84 is redundant because all proteins must be expressed endogenously or exogenously. Delete “endogenously or exogenously”. The phrase “further comprises two single target sites for insertion of an exogenous nucleic acid encoding a TCR chain, wherein each target site is respectively a synthetic or native genomic receiver site for integration” in claim 84 is redundant because any two sequences in the genome of a T-cell can be used as homology arms for inserting exogenous DNA using a homology vector. Any sequence in the genome can be used for recombinase-mediated recombination or site directed homologous recombination. There is nothing in the phrase that further limits the structure or function of the target sites for the homology arms of a homology vector. Claim 84 on pg 3, lines 4-11, in the response filed 1-22-26 never clearly sets forth that an exogenous sequence encoding a TCR alpha, beta, delta, or gamma chain has been inserted into the genome of the T-cell. Just saying the genome of the T-cell has target sites capable of receiving a homology vector comprising an exogenous sequence encoding a TCR alpha, beta, delta, or gamma chain is meaningless for reasons set forth above. The metes and bounds of when exogenous sequences encoding a TCR alpha, beta, delta, or gamma chains are “a single complementary pair” in line 10 on pg 3 of claim 84 cannot be determined. The metes and bounds of a “genetic receiver” that is a synthetic construct for “recombinase-mediated cassette exchange”, a synthetic construct for “site directed homologous recombination”, or a “native target site” in claim 84 cannot be determined. Again, these three categories of “genetic receivers” do not further limit the genome of the T-cells because any part of the genome of the T-cell can be used as homology arms for a homology vector, recombinase-mediated recombination, or site directed homologous recombination. If the “genetic donor vector” is the second part of the system, then the T-cells should be item A) and the vector should be item B). Just say ---B) an isolated vector--- and clearly set forth the structure/function of the vector, e.g. ---comprising a nucleic acid sequence encoding a TCR alpha, beta, delta or gamma chain---. The metes and bounds of when exogenous sequences encoding analyte TCR chains are “a single complementary pair” in line 21 on pg 3 of claim 84 cannot be determined. The meaning of “wherein the one or more ORFs encoded by the [vector] recombine with the first genomic receiver site when introduced into the eTPC, and integrates” in line 23 on pg 3 of claim 84 cannot be determined. This appears as though applicants attempting to embed product-by-process language into the vector within item B) of the system of claim 84. Specifically, it appears as though applicants are attempting to say the exogenous sequence in the vector has “recombined” and “integrated”. If applicants are attempting to add product-by-process language into item B) of claim 84, this is ill-advised because of the numerous issues with what is already a bulky and confusing claim. If applicants are simply attempting to set forth a capability of the vector, then just say that e.g. ---wherein the nucleic acid sequence encoding a TCR alpha, beta, delta or gamma chain encoded by the vector is capable of integrating into the genome of the isolated mammalian T-cell---. If applicants are attempting to say the genome of the T-cell already has the exogenous sequences, then just say that, e.g. an isolated mammalian T-cell whose genome comprises inactivated TCR alpha, beta, delta, and gamma genes and exogenous nucleic acid sequences encoding exogenous TCR alpha, beta, delta, and gamma chains, wherein the T-cell does not express endogenous TCR alpha, beta, delta, or gamma chains and DOES express the exogenous TCR alpha, beta, delta, and gamma chains---. The remainder of claim 84 still has numerous clarity issues at the bottom of pg 3 and throughout pg 4. For example, the limitations regarding CD3 on pg 4, lines 4-9, should be with the CD3 language on pg 2, last three lines. The limitations regarding the structure of the T-cells on pg 4, lines 10-20, should be with the T-cells in item A) on pg 2 of claim 84. If there are only two components to the “system” of claim 84, i.e. A) isolated mammalian T-cells; and B) a vector, then claim 84 is more aptly a composition claim, e.g. ---A composition comprising: A) isolated mammalian T-cells; and B) a vector---. If the vector has already been integrated into the genome of the T-cells, then the “system” is actually just isolated mammalian T-cells, which should be reflected in the preamble of claim 84, e.g. ---An isolated mammalian T-cell. Therefore, those of skill would not be able to determine when they were infringing on the claim.
Response to arguments
Applicants argue the amendment overcomes the rejections. Applicants’ argument is not persuasive for reasons set forth above.
Applicants argue the analyte antigenic molecule is a protein or a metabolite expressed by a cell as described on pg 389 (pg 16). Applicants’ argument is not persuasive. Any protein can be an antigen. Just call it a protein or an antigen. The phrase is jargon and the term “analyte” in the phrase is meaningless.
Applicants’ discussion of the analyte being a target for TCRs (pg 16) is meaningless because the “analyte antigenic molecule” is optional.
Applicants argue “recombinase mediated cassette exchange” is well-known therefore conclude “genomic recievers” for “recombinase mediated cassette exchange” are clear. Applicants’ argument is not persuasive because any two sequences in the genome of a T-cell can be used as homology arms for inserting exogenous DNA using a homology vector. Any sequence in the genome can be used for recombinase-mediated recombination or site directed homologous recombination. There is nothing in the phrase that further limits the structure or function of the target sites for the homology arms of a homology vector.
Applicants other discussions are noted but are not persuasive for reasons set forth above.
B) The metes and bounds of an “eTPC-t” or “eTPC” that “lacks endogenous surface expression of [an] antigen presenting complex (aAPX)” that “has been engineered such that endogenous surface expression of the HLA class I, HLA class II, CD1, MR1 or aAM has been inactivated” does not necessarily indicate a genetic modification because the proteins can be inactivated by binding other proteins to them or by chemical means. The claim fails to set forth the genetic modification, the structure of the genome of the cell, or the function of the genetic modification within the cell.
The metes and bounds of an inactivated “antigen presenting complex” (aAPX) cannot be determined. Pg 11, line 22-25, describes an antigen-presenting complex that is “a protein that is expressed and presented on the cell surface by nucleated cells from genes/ORF encoding genomic DNA and/or a specific introduced genetic sequence. The APX presents a cargo, being either a peptide or other metabolite molecules”. Pg 111, lines 22-25, does not mention how a “non-HLA” is part of a “complex” required to present the antigen. Pg 111, lines 22-25, does not explain how a “complex” of a “non-HLA” molecule and antigen is endogenously expressed in the cell or how to make sure the cell “lacks endogenous surface expression” of the “aAPX”. The concept does not make sense because the cell does not “endogenously” express an “antigen presenting complex”, so it cannot lack “endogenous” expression of an “antigen presenting complex” as claimed. While the non-HLA may be endogenously expressed, the antigen is not because it is recognized as foreign by the non-HLA molecule. However, the metes and bounds of a “non-HLA antigen presenting complex” also does not make sense because it is unclear what proteins other than HLA molecules “present” antigens in a complex for recognition by the immune system. While the claim requires the cell “lacks endogenous surface expression” of an “aAPX”, it is unclear how the cell DOES exhibit “endogenous surface expression” of an “aAPX”, so it cannot be determined what genetic modification or engineering must occur to prevent “endogenous surface expression” of an “aAPX”.
Pg 6, line 26, through pg 7, line 21, discuss unconventional αβ T-cells and says “The non-HLA-restricted, or ‘unconventional’, forms of ap T-cells have very different molecular antigen targets. These unconventional ap T-cells do not engage classical HLA complexes, but rather engage conserved HLA-like proteins such as the CD1 family or MR1. The CD1 family comprises four forms involved in antigen cross-presentation (CD1a,b,c and d).” However, the specification does not define the metes and bounds of a “non-HLA” capable of forming an “aAPX” with a peptide. Merely saying CD1a, b, c or d are possible “non-HLA” or “unconventional” molecules without defining the function of the proteins required to form a complex capable of presenting an antigen in a complex is not a definition. It remains unclear what function the “non-HLA” molecules must have or what structures are encompassed by the term in context of the “aAPX”. It is unclear what structures/functions define the “non-HLA” molecules within the “non-HLA” “aAPX”.
The structures/functions associated with an “nonHLA” “aAPX” cannot be determined. It cannot be determined how/why/when a “nonHLA” “aAPX” is endogenously expressed, so it cannot be determined what genetic modifications or “engineering” are required to obtain a cell that lacks “endogenous” expression of a “nonHLA” “aAPX”. The metes and bounds of non-HLA molecules that are required to present an antigen in an “aAPX” cannot be determined.
Response to arguments
Applicants’ discussions of aAPX are noted but are not persuasive for reasons set forth above.
C) The metes and bounds of an “analyte antigenic molecule” in claim 84 are unknown. The structures/functions associated with such a molecule are not disclosed in the specification or the art at the time of filing. The claim says the aAM is “a. a polypeptide or complex of polypeptides translated from the analyte antigenic molecule open reading frames (ORF(s)), b. a peptide obtained or isolated from a polypeptide translated from the analyte antigenic molecule ORF(s), c. a peptide obtained or isolated from altering a component A proteome,d. a polypeptide obtained or isolated from altering a component A proteome, or e. a metabolite obtained or isolated from altering a component A metabolome”, but the meaning of each cannot be discerned. E.g. it is unclear whether “a polypeptide or complex of polypeptides translated from the analyte antigenic molecule open reading frames” is just one or more peptide or if something else is required to meet the limitation. It is unclear how the “polypeptide or complex of polypeptides” in a) differ from the peptide in b). The metes and bounds of a peptide obtained “from altering a component A proteome” in c) or d) cannot be determined. The metes and bounds of metabolites obtained “from altering a component A metabolome” are not disclosed.
Response to arguments
Applicants’ discussions of aAPX are noted but are not persuasive for reasons set forth above.
D) The metes and bounds of α, β, Δ, or γ “analyte TCR chains” in claim 84 cannot be determined. It is unclear whether they are just α, β, Δ, or γ TCR chains or if something else is required to make them “analytes”. If the α, β, Δ, or γ “analyte TCR chains” are something more than just α, β, Δ, or γ TCR chains, then the metes and bounds of what define α, β, Δ, or γ TCR chains as “analytes” cannot be determined.
Response to arguments
Applicants’ discussions of analyte TCR chains are noted but are not persuasive for reasons set forth above. The concept is still in claim 84.
E) The metes and bounds of a “synthetic construct designed for recombinase mediated cassette exchange” or “synthetic construct designed for site-directed homologous recombination” cannot be determined. It is unclear whether it is a nucleic acid sequence or not. It is unclear what structures or functions make it “designed for” recombinase exchange or homologous recombination. It is unclear whether the cell in claim 84 contains the ORF encoding a TCR (inserted into a “receiver site” within the genome of the cell) or not and whether the ORF is within the “synthetic construct”.
Response to arguments
Applicants’ discussions of RMCE are noted but are not persuasive for reasons set forth above.
F) The structures/functions of the “genetic donor vector” in claim 84 cannot be determined. The claim says it is a “genetic donor vector” for site directed integration of an open reading frame (ORF), but the structures/functions required for site directed integration of an ORF are not disclosed in the specification or the art at the time of filing.
It is unclear whether the “donor vector” has been integrated into the genome of the cell, if it is merely present in the cell, or if it is merely present in the “system”.
The metes and bounds of what is encoded by the “genetic donor vector” cannot be determined.
Response to arguments
Applicants’ discussions of the vector are noted but are not persuasive for reasons set forth above.
G) The functional language of “recombines with the second genomic receiver site when introduced into the eTPC and integrates (i) a single ORF encoding at least one analyte TCR chain (eTPC-x) of TCR alpha, TCR beta, TCR delta, or TCR gamma or (ii) two ORFs encoding the single complementary pair of analyte TCR chains, wherein ORF (i) or (ii) optionally encodes a selection marker of integration, wherein a single copy of each ORF encoding the at least one analyte TCR chain or the single complementary pair of analyte TCR chains is integrated in the genome of component A, and the at least one analyte TCR chain or the pair of analyte TCR chains are expressed on component A as a TCR surface protein in complex with a CD3 complex (TCRsp), wherein the CD3y, CD36, CD3s, and CD3( are conditionally presented on the surface of the eTPC-t to assemble into the CD3 complex when the eTPC-t expresses a complementary pair of alpha and beta TCR chains or a complementary pair of gamma and delta TCR chains, wherein component A further comprises component F, which is a synthetic genomic TCR-stimulation response element selected from:(a) a single component synthetic construct comprising at least one native promoter or at least one synthetic promoter, and at least one reporter; or (b) a multi-component synthetic construct comprising at least one native promoter or at least one synthetic promoter, and at least one reporter, wherein activation of the synthetic genomic TCR-stimulation response element is dependent on at least one signal transduction pathway selected from a synthetic pathway, a native pathway, or a combination thereof, and wherein the component F is induced by engagement of an αβ or γΔ TCR with cognate antigen” in claim 84 does not make scientific, legal, or grammatical sense. It is so confusing and convoluted that the structures/functions of the vector cannot be discerned.
Response to arguments
Applicants’ discussion of this is noted but fails to address the lack of scientific, legal, or grammatical logic in the convoluted phrase.
H) The final structure/function of the “population of engineered TCR-presenting cells” capable of being made by the system of claim 84 (line 2) cannot be determined. It is unclear how they are engineered, and whether they are engineered by anything in the “system”. It is unclear if they encompass any cells that express a TCR or if they must be T-cells.
Response to arguments
Applicants’ discussion of this is noted but fails to teach the metes and bounds of the cells within the system.
I) It is unclear whether the TCR-presenting cells (eTPC-t) in line 2 of claim 84 are part of the system or not.
Response to arguments
Applicants do not appear to discuss this rejection.
J) The distinction between “eTPC-t” and “eTPC” in lines 2 and 5 of claim 84 cannot be determined.
Response to arguments
Applicants do not appear to discuss this rejection.
K) Claim 86 requires the system contains a 2nd vector, but the structure and function of the 2nd vector cannot be determined. The claim says the vector is for site-directed integration of one or more ORFs encoding analyte TCR chains into the second genomic receiver site that delivers (i) a single ORF encoding at least one analyte TCR chain of alpha, beta, delta, or gamma or (ii) two ORFs encoding a single complementary pair of analyte TCR chains selected from the group consisting of alpha, beta, delta and gamma into component D, wherein ORF (i) or (ii) optionally encodes a selection marker of integration, wherein after integration of the ORF into the eTPC genome at the second genomic receiver site and the analyte TCR chains are expressed on the eTPC as a TCR surface protein in complex with a CD3 complex (TCRsp), wherein the CD3y, CD3d, CD3s, and CD3g are conditionally presented on the surface of the eTPC-t to assemble into the CD3 complex when the eTPC-t expresses a complementary pair of alpha and beta TCR chains or a complementary pair of gamma and delta TCR chains”. But the claim is so confusing and convoluted that the structures/functions of the vector cannot be discerned. The metes and bounds of “analyte TCR chains” cannot be determined for reasons set forth above. The different components and how/whether they are incorporated into the isolated mammalian cell cannot be discerned.
Response to arguments
Applicants discussion of claim 86 is noted but is not persuasive.
L) The metes and bounds of “the first and second genomic receiver sites are each a synthetic construct designed for recombinase mediated cassette exchange (RMCE)” in claim 88 cannot be determined. The specification and the art at the time of filing do not teach the structures/functions associated with a construct designed for RMCE. The specification and the art at the time of filing do not teach the structures/functions associated with RMCE. The concept does not make sense because the “synthetic construct” is inserted into a “receiver site”. The “synthetic construct” cannot further limit the “receiver site” because it is inserted into the “receiver site”.
Response to arguments
Applicants discussion of claim 88 is noted but is not persuasive.
M) The metes and bounds of “one or more additional TCR co-receptors” in claim 91 cannot be determined. The specification and the art at the time of filing do not define the phrase, and the metes and bounds cannot be envisioned.
Response to arguments
Applicants discussion of claim 91 is noted but is not persuasive.
N) The metes and bounds of the phrase “wherein the first and second genomic receiver site each comprises at least one of the following genetic elements:a. heterospecific recombinase sites,b. homologous arms,c. an eukaryotic promoter,d. an eukaryotic conditional regulatory element,e. an eukaryotic terminator,f. a selection marker,g. a splice acceptor site,h. a splice donor site,i. a non-protein coding gene,j. an insulator,k. a mobile genetic element” in claim 93 cannot be determined. The metes and bounds of “genomic receiver site” cannot be determined. It is unclear what the elements listed in claim 93 are further limiting. It is unclear whether they are in the APCs, the “complex”, or the vector of claim 84. It is unclear when a “regulatory element” is a “conditional” regulatory element as required in claim 93. It is unclear when a gene is a “non-protein coding gene” as required in claim 93. It is unclear when a “genetic element” is a “mobile” genetic element as required in claim 93. The metes and bounds of a “viral self-cleaving peptide element” cannot be determined.
Response to arguments
Applicants discussion of claim 93 is noted but is not persuasive.
New rejections
O) The metes and bounds of a genomic receiver site “for integration of two or more ORF and comprise [ ] two Eukaryotic promoters, a pair of heterospecific recombinase sites, two or more Kozak consensus sequences, two selection markers, and two Eukaryotic terminators” in claim 122 are unclear. Target sites for a homology vector, recombinase sites, or site directed homologous recombination are simply nucleic acid sequences. They may be part of a promoter but they do not comprise two promoters. The target sites may be recombinase sites, but it is unclear when they are “heterospecific”. Target sites for a homology vector, recombinase sites, or site directed homologous recombination cannot be “two or more Kozak consensus sequences” or “selection markers” or “two eukaryotic terminators”. The concept does not make scientific, legal, or logical sense, and it is unclear how the claim further limits the structure/function of the “receiver sites” within the genome of the isolated mammalian cell.
P) The concept of RMCE sites in claim 123 is indefinite for reasons set forth above.
Q) The metes and bounds of a “at least one of the first and second genomic receiver sites is for integration of two or more ORF and comprises the following genetic elements in order:a first Eukaryotic promoter,a first heterospecific recombinase site,a first Kozak consensus sequence a first selection marker,a Eukaryotic bidirectional terminator,a second selection marker,a second Kozak consensus sequence,a heterospecific recombinase site, anda second Eukaryotic promoter.wherein second selection marker, the second Kozak consensus sequence, and the second Eukaryotic promoter are encoded in the antisense direction” in claim 124 cannot be determined. The structure/function of the “genomic receivers” cannot be determined for reasons set forth above. Target sites for a homology vector, recombinase sites, or site directed homologous recombination are simply nucleic acid sequences. They may be part of a promoter but they do not comprise two promoters. The target sites may be recombinase sites, but it is unclear when they are “heterospecific”. Target sites for a homology vector, recombinase sites, or site directed homologous recombination cannot be “two or more Kozak consensus sequences” or “selection markers” or “two eukaryotic terminators”. The concept does not make scientific, legal, or logical sense, and it is unclear how the claim further limits the structure/function of the “receiver sites” within the genome of the isolated mammalian cell.
R) The metes and bounds of “wherein the genetic donor vector comprises the following elements in order:a first heterospecific recombinase site,a first Kozak consensus sequence,a cloning site for introduction of two or more ORF, with eukaryotic terminators,encoding one or more TCR chains and/or element a selection marker of integration;a second Kozak consensus sequence, wherein the second Kozak consensus sequence is encoded in the antisense direction;a second heterospecific recombinase site,an antibiotic resistance cassette, anda bacterial origin of replication” in claim 125 cannot be determined. The structure/function of the “genomic receivers” cannot be determined for reasons set forth above. Target sites for a homology vector, recombinase sites, or site directed homologous recombination are simply nucleic acid sequences. They may be part of a promoter but they do not comprise two promoters. The target sites may be recombinase sites, but it is unclear when they are “heterospecific”. Target sites for a homology vector, recombinase sites, or site directed homologous recombination cannot be “two or more Kozak consensus sequences” or “selection markers” or “two eukaryotic terminators”. The concept does not make scientific, legal, or logical sense, and it is unclear how the claim further limits the structure/function of the “receiver sites” within the genome of the isolated mammalian cell.
S) Claim 126 does not further limit claim 125 because it further limits the ORF, but there is no ORF in the system in claim 125. Claim 125 merely says the “genomic receivers” are for receiving an ORF without ever requiring the presence of an ORF in the system or the vector within the system. Therefore, claim 126 cannot further limit claim 125 since claim 125 does not require an ORF.
A proper search cannot be done at this time because the claims are so unclear.
Examination of the claims under written description and enablement cannot be done at this time because the claims are so unclear.
Double Patenting
Terminal disclaimers were filed over applications 16347684, now US Patent 12012610, and 16347716, now abandoned.
Conclusion
No claim is allowed.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
Prosecution Insights