DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed December 4, 2023 is pending.
Claims 4, 5, 8, 12, 14, 16-18, 21, 25, 28, 29, and 32-35 are canceled.
Claims 1-3, 6, 7, 9-11, 13, 15, 19, 20, 22-24, 26, 27, 30, 31, and 36 are pending.
Claims 1, 19, and 36 are independent claims.
It is noted that in the Supplemental Response to the Restriction Requirement filed 02/03/2026 the Applicant pointed out that the Examiner erroneously included claim 36 in Group II in the Restriction Requirement mailed on 12/02/2025. The Examiner agrees that claim 36 was inadvertently included in Group II given that it is drawn to a method for producing a cryopreserved Treg or population of Tregs and not a method of preventing and/or treating disease. Claim 36 is now correctly included in Group I.
Applicant’s election without traverse of Group I (claims 1-3, 6, 7, 9-11, 13, 15, 19, 20, 22-24, 26, 27, and 36, drawn to a method of preserving CD62L expression in a regulatory T cell (Treg) population that has been cryopreserved; a cryopreserved engineered Treg population comprising an exogenous polynucleotide encoding a FOXP3 polypeptide; a Treg population; a pharmaceutical composition; and a method for producing a cryopreserved Treg or population of Tregs); and the species of step "(A) step (b) comprises the following steps of: (bi) suspending said Treg population in a cryopreservation media; (bii) freezing the Treg population of (bi); and (biii) storing the Treg population of (bii) at a temperature below - 130°C" as the method of cryopreservation in the reply filed on January 29, 2026 is acknowledged.
Claims 30 and 31 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions.
Claims 1-3, 6, 7, 9-11, 13, 15, 19, 20, 22-24, 26, 27, and 36 are currently under consideration.
Claim Objections
Claims 27 and 36 are objected to because of the following informalities:
Claim 27 recites “A pharmaceutical composition comprising a Treg population according to claim 19” where it should recite “A pharmaceutical composition comprising the Treg population according to claim 19” in lines 1 and 2.
Claim 36 recites “A method for producing a cryopreserved Treg or population of Tregs having a level of CD62L comparable to a corresponding non-cryopreserved Treg or population of Tregs” where it should recite “A method for producing a cryopreserved Treg or population of Tregs having a level of CD62L expression comparable to a corresponding non-cryopreserved Treg or population of Tregs” in lines 1 and 2.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Indefinite language
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 1-3, 6, 7, 9-11, 13, 15, 19, 20, 22-24, 26, 27, and 36 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 1 recites “A method of preserving CD62L expression in a regulatory T cell (Treg) population that has been cryopreserved, comprising introducing a polynucleotide encoding a FOXP3 polypeptide into the Treg population prior to cryopreservation” in lines 1-3. It is unclear whether the term “comprising” in line 2 is referring to the method or the Treg population that has been cryopreserved. Amending the claim to recite “A method of preserving CD62L expression in a regulatory T cell (Treg) population that has been cryopreserved, the method comprising introducing a polynucleotide encoding a FOXP3 polypeptide into the Treg population prior to cryopreservation” in lines 1-3 would obviate this part of the rejection.
Claim 2 recites “a corresponding non-engineered Treg population after cryopreservation” in lines 2 and 3. Claim 2 is dependent on claim 1 which does not recite “an engineered Treg population.” Therefore, the limitation of claim 2 that is drawn to a “non-engineered Treg population” lacks antecedent basis. Amending claim 2 to recite “a corresponding Treg population after cryopreservation, wherein the corresponding Treg population has not had a polynucleotide encoding a FOXP3 polypeptide introduced to it" would obviate this part of the rejection.
Claims 3, 6, and 9 recite “the polynucleotide encoding FOXP3.” However, claim 6 is dependent on claim 3 and claims 3 and 9 are dependent on claim 1 which recites “a polynucleotide encoding a FOXP3 polypeptide” not “a polynucleotide encoding FOXP3.” Therefore, there is no antecedent basis for the limitation of “the polynucleotide encoding FOXP3” as recited in claims 3, 6, and 9. Amending claims 3, 6, and 9 to recite “the polynucleotide encoding the FOXP3 polypeptide” instead of “the polynucleotide encoding FOXP3” would obviate this part of the rejection.
Claim 6 also recites “wherein in part (c): (i) the polynucleotide encoding the FOXP3 polypeptide and the polynucleotide encoding the exogenous TCR or CAR are provided by a single expression vector, and/or (ii) there is an internal self-cleaving sequence between the polynucleotide encoding FOXP3 and the polynucleotide encoding the exogenous TCR or CAR” in lines 1-6. However, claim 6 is dependent on claim 3 which recites “and/or (c) the method further comprises introducing a polynucleotide encoding an exogenous T cell receptor (TCR) or a polynucleotide encoding a chimeric antigen receptor (CAR) into the Treg population” in lines 4-7. Therefore, given the broadest reasonable interpretation, claim 3 is read as not necessarily introduction of a polynucleotide encoding an exogenous T cell receptor (TCR) or a polynucleotide encoding a chimeric antigen receptor (CAR) into the Treg population. Thus, the limitation of claim 6 which is drawn to the polynucleotide encoding the exogenous TCR or CAR of claim 3 lacks antecedent basis. Amending claim 3 to recite “and (c) the method further comprises introducing a polynucleotide encoding an exogenous T cell receptor (TCR) or a polynucleotide encoding a chimeric antigen receptor (CAR) into the Treg population” would obviate this part of the rejection.
Claim 7 recites “the vector” in line 1. However, claim 7 is dependent on claim 6 which recites “a single expression vector” not “a single vector.” Therefore, there is no antecedent basis for the limitation of “the vector” as recited in claim 7. Amending claim 7 to recite “the expression vector” in line 1 would obviate this part of the rejection.
Claim 9 also recites “wherein the polynucleotides encoding FOXP3 and/or the exogenous TCR or CAR are introduced” in lines 1 and 2. Therefore, claim 9 can be read as “wherein the polynucleotides encoding FOXP3 or the exogenous TCR or CAR.” However, while the use of the plural term “polynucleotides” in line 2 assumes that the claim is referring to two separate polynucleotide molecules, the use of the term “or” following the term “FOXP3” means that the claim is referring to a single polypeptide. Therefore, it is unclear how the same limitation can be referring to more than one polynucleotide and one polynucleotide at the same time. Amending claim 9 to recite “wherein the polynucleotide encoding the FOXP3 polypeptide and/or the polynucleotide encoding the exogenous TCR or CAR are/is introduced” in lines 1 and 2 would obviate this part of the rejection.
Claims 9, 11, and 15 recite the terms “preferably” and/or “optionally.” The recitation of the terms “preferably” and/or “optionally” in claims 9, 11, and 15 render the claims indefinite because it is unclear whether the limitation(s) following the phrases are part of the claimed invention. See MPEP § 2173.05(d). Amending the claims to delete the “preferably”/“optionally” clauses would obviate this part of the rejection.
Claim 10 recites the limitation “further comprising the steps of (a) introducing a polynucleotide encoding a FOXP3 polypeptide into the Treg population” in lines 1-3. Claim 10 is dependent on claim 1 which already recites the method step of “introducing a polynucleotide encoding a FOXP3 polypeptide into the Treg population” in lines 2 and 3. It is unclear whether step (a) of claim 10 is in addition to the same step already recited in claim 1 or if it is referring to the same step already recited in claim 1. If it is the latter, then the limitation is not further limiting. If it is the former, it is unclear why the step needs to be repeated. Amending claim 10 to recite “further comprising the step of cryopreserving said T reg population” would obviate this part of the rejection.
Claim 10 also recites that the method of claim 1 “further comprising the steps of (a) introducing a polynucleotide encoding a FOXP3 polypeptide into the Treg population; and (b) cryopreserving said Treg population” in lines 1-4. Claim 10 is dependent on claim 1 which only recites the active method step of “introducing a polynucleotide encoding a FOXP3 polypeptide into the Treg population prior to cryopreservation” in lines 2 and 3. However, the recitation of “(a)” and “(b)” implies that these steps are meant to be completed in a specific order namely, step “(a)” followed by step “(b).” However, given that neither claims 1 or 10 recite (or at the very least it is unclear) that the step of claim 1 has to be preformed first or that it is step “(a),” it is unclear what the order of steps for claim 10 are supposed to me. Furthermore, the recitation of “(a)” and “(b)” lacks antecedent basis because claims 1 and 10 do not reference any particular order for the step of claim 1. Amending claim 10 to recite that the method of claim 1 “further comprising the step cryopreserving said Treg population after introducing the polynucleotide encoding the FOXP3 polypeptide into the Treg population” would obviate this part of the rejection.
Claim 11 recites “further comprising a step of: isolating a Treg population from a sample prior to introducing the polynucleotide encoding a FOXP3 polypeptide into said Treg population; and/or thawing said Treg population after cryopreservation” in lines 1-4. Therefore, claim 11 can be read as “further comprising a step of: isolating a Treg population from a sample prior to introducing the polynucleotide encoding a FOXP3 polypeptide into said Treg population; and thawing said Treg population after cryopreservation.” However, while the use of the phrase “a step” in line 1 assumes that the claim is referring to a single step while the term “and” in line 3 makes it so the same is referencing two steps. Therefore, it is unclear how the same limitation can be referring to a single step and then recite more than one step at the same time.
Claim 11 also recites “a Treg population” and “a FOXP3 polypeptide” in lines 2 and 3, respectively. Claim 11 dependent on claim 10 which depends on claim 1 which recites “introducing a polynucleotide encoding a FOXP3 polypeptide into the Treg population” in lines 2 and 3. It is unclear whether the Treg population and the FOXP3 polypeptide recited in claim 11 are in addition to or are the same as those already recited in claim 1.
Claim 11 also recites “isolating a Treg population from a sample prior to introducing the polynucleotide encoding a FOXP3 polypeptide into said Treg population” in lines 2 and 3. However, claim 11 is dependent on claim 10 which is dependent on claim 1 which recites that the “Treg population has been cryopreserved” and that the “polynucleotide encoding a FOXP3 polypeptide” is introduced “into the Treg population prior to cryopreservation.” Therefore, it is unclear if the isolation step of claim 11 happens before or after cryopreservation.
Amending claim 11 to recite “further comprising the steps of: isolating the Treg population from a sample prior to cryopreservation and prior to introducing the polynucleotide encoding the FOXP3 polypeptide into said Treg population; and thawing said Treg population after cryopreservation” would obviate this part of the rejection.
Claim 13 recites “and/or (B) the method further comprises the steps of: pre-chilling said Treg population, and/or any one or more reagents and devices to be used in the cryopreservation step, prior to step (b); cryopreserving said Treg population according to step (b) at a controlled rate of freezing of approximately -1 °C per minute; and/or storing the Treg population at -80°C for up to 24 hours prior to step (biii)” in lines 6-12. Therefore, claim 13 can be read as “or (B) the method further comprises the steps of…storing the Treg population at -80°C for up to 24 hours prior to step (biii).” However, if the term “or” is used in line 6 instead of “and” then the reference to “step (biii)” in line 12 lacks antecedent basis. Amending claim 13 to replace the term “and/or” with “and” in line 6 or to delete the reference to “step (biii)” in line 12 would obviate this part of the rejection.
Claim 15 also recites “wherein: (a) thawing the Treg population comprises warming the Treg population from a temperature below -130°C to a temperature of between approximately 0-10°” in lines 3 and 4. However, claim 15 is dependent on claim 11 which recites “and/or thawing said Treg population after cryopreservation” in lines 3 and 4. Therefore, given the broadest reasonable interpretation, claim 11 is read as not necessarily requiring the thawing step. Thus, the limitation of claim 15 which is drawn to the thawing step of claim 11 lacks antecedent basis. Amending claim 11 to recite “and thawing said Treg population after cryopreservation” would obviate this part of the rejection.
Claim 15 also recites “the Treg population is isolated by selecting for:(i) CD4+CD25+CD127- and/or CD4+CD25+CD127low cells; or (ii) CD4+CD25hiCD127- and/or CD4+CD25+CD127 low cells” in lines 7-9. Therefore, claim 15 can be read as “the Treg population is isolated by selecting for: (i) CD4+CD25+CD127low cells; or (ii) CD4+CD25+CD127 low cells.” However, if the claim is read like this, then these limitations are redundant. Amending claim 15 to recite “the Treg population is isolated by selecting for:(i) CD4+CD25+CD127- and CD4+CD25+CD127low cells; or (ii) CD4+CD25hiCD127- and CD4+CD25+CD127 low cells” would obviate this part of the rejection.
Claim 19 recites “the engineered Treg population” and “a corresponding non-engineered Treg population after cryopreservation” in lines 2-4. Claim 19 is an independent claim and does not recite “an engineered Treg population” prior to the limitation “the engineered Treg population.” Therefore, these limitations lack antecedent basis. Amending claim 19 to recite “wherein the Treg population comprising the exogenous polynucleotide encoding the FOXP3 polypeptide has higher CD62L expression after cryopreservation than a corresponding Treg population that does not comprise an exogenous polynucleotide encoding a FOXP3 polypeptide after cryopreservation" would obviate this part of the rejection.
Claim 20 recites “the exogenous polynucleotide encoding FOXP3” in line 5. However, claim 20 is dependent on 19 which recites “an exogenous polynucleotide encoding a FOXP3 polypeptide” not “an exogenous polynucleotide encoding FOXP3.” Therefore, there is no antecedent basis for the limitation of “the exogenous polynucleotide encoding FOXP3” as recited in claim 20. Amending claim 20 to recite “the exogenous polynucleotide encoding the FOXP3 polypeptide” instead of “the exogenous polynucleotide encoding FOXP3” would obviate this part of the rejection.
Claim 23 recites “wherein (a) the polynucleotide encoding the FOXP3 polypeptide and the polynucleotide encoding the exogenous TCR or the CAR are provided by a single expression vector; and/or (b) there is an internal self-cleaving sequence between the polynucleotide encoding FOXP3 and the polynucleotide encoding the exogenous TCR or CAR” in lines 4-6. Therefore claim 23 can be read as “wherein (a) the polynucleotide encoding the FOXP3 polypeptide and the polynucleotide encoding the exogenous TCR or the CAR are provided by a single expression vector; or (b) there is an internal self-cleaving sequence between the polynucleotide encoding FOXP3 and the polynucleotide encoding the exogenous TCR or CAR.” However, if claim 23 is read this way, then there is no antecedent basis for the limitation of “there is an internal self-cleaving sequence between the polynucleotide encoding FOXP3 and the polynucleotide encoding the exogenous TCR or CAR” in lines 5 and 6. This is because, in order for a sequence to be interested between two polynucleotides, the polynucleotides need to first be present together within a single polynucleotide or vector. Therefore, since neither claim 23 or claim 22, which claim 23 is dependent on, do not necessarily recite that the two polynucleotides are present together within a single polynucleotide or vector, there is no antecedent basis for the limitation of “there is an internal self-cleaving sequence between the polynucleotide encoding FOXP3 and the polynucleotide encoding the exogenous TCR or CAR” as recited in lines 5 and 6 of claim 23.
Amending claim 23 to recite “wherein (a) the polynucleotide encoding the FOXP3 polypeptide and the polynucleotide encoding the exogenous TCR or the CAR are provided by a single expression vector; and (b) there is an internal self-cleaving sequence between the polynucleotide encoding FOXP3 and the polynucleotide encoding the exogenous TCR or CAR” would obviate this part of the rejection.
Claim 24 recites “the vector” in line 2. However, claim 24 is dependent on claim 23 which recites “a single expression vector” not “a single vector.” Therefore, there is no antecedent basis for the limitation of “the vector” as recited in claim 24. Amending claim 24 to recite “the expression vector” in line 2 would obviate this part of the rejection.
Claim 36 recites “A method for producing a cryopreserved Treg or population of Tregs having a level of CD62L comparable to a corresponding non-cryopreserved Treg or population of Tregs comprising (a) introducing a polynucleotide encoding FOXP3 into a Treg or population of Tregs and (b) cryopreserving said Treg or population of Tregs” in lines 1-4. It is unclear whether the term “comprising” in line 2 is referring to the method or the non-cryopreserved Treg or population of Tregs. Amending the claim to recite “A method for producing a cryopreserved Treg or population of Tregs having a level of CD62L comparable to a corresponding non-cryopreserved Treg or population of Tregs, the method comprising (a) introducing a polynucleotide encoding FOXP3 into a Treg or population of Tregs and (b) cryopreserving said Treg or population of Tregs” would obviate this part of the rejection.
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.
Written Description
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 1-3, 6, 7, 9-11, 13, 15, 19, 20, 22-24, 26, 27, 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 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are drawn to (1) a method of preserving CD62L expression in a regulatory T cell (Treg) population that has been cryopreserved, comprising introducing a polynucleotide encoding a FOXP3 polypeptide into the Treg population prior to cryopreservation; (2) a cryopreserved engineered Treg population comprising an exogenous polynucleotide encoding a FOXP3 polypeptide, wherein the engineered Treg population has higher CD62L expression after cryopreservation than a corresponding non-engineered Treg population after cryopreservation; and (3) a method for producing a cryopreserved Treg or population of Tregs having a level of CD62L comparable to a corresponding non-cryopreserved Treg or population of Tregs comprising (a) introducing a polynucleotide encoding FOXP3 into a Treg or population of Tregs and (b) cryopreserving said Treg or population of Tregs.
The Applicant has disclosed that the FOXP3 polypeptide may comprise an amino acid sequence which is at least 80% identical to SEQ ID NO. 1 or a functional fragment thereof (e.g. see page 7, lines 15-17). The Applicant has also disclosed that a "FOXP3 polypeptide" is a polypeptide having FOXP3 activity i.e. a polypeptide able to bind FOXP3 target DNA and function as a transcription factor regulating development and function of Tregs (e.g. see page 18, line 33 – page 19, line 2). Particularly, a FOXP3 polypeptide may have the same or similar activity to wildtype FOXP3 (SEQ ID NO. 1), e.g. may have at least 40, 50, 60, 70, 80, 90, 95, 100, 110, 120, 130, 140 or 150% of the activity of the wildtype FOXP3 polypeptide (e.g. see page 18, line 33 – page 19, line 2). FOXP3 polypeptide includes functional fragments, variants, and isoforms thereof, e.g. of SEQ ID NO. 1. (e.g. see page 19, lines 10-12).
The Applicant has also disclosed that a "functional fragment of FOXP3" may refer to a portion or region of a FOXP3 polypeptide or a polynucleotide encoding a FOXP3 polypeptide that has the same of similar activity to the full-length FOXP3 polypeptide or polynucleotide. The functional fragment may have at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the activity of the full-length FOXP3 polypeptide or polynucleotide (e.g. see page 19, lines 13-17). The Applicant has also disclosed that a person skilled in the art would be able to generate functional fragments based on the known structural and functional features of FOXP3 (e.g. see page 19, lines 17-19). Further, a N and C terminally truncated FOXP3 fragment is described within WO2019/241549, for example, having the sequence SEQ ID NO. 5 (e.g. see page 19, lines 21-23).
The Applicant has also disclosed that FOXP3 variants having amino acid substitutions at amino acid 418 and/or 422 of SEQ ID NO. 1, for example S418E and/or S422A, as described in WO2019/241549 (incorporated herein by reference) and are set out in SEQ ID NOs: 2-4, which represent the aa418, aa422, and aa418 and aa422 mutants respectively (e.g. see page 20, lines 2-5). Furthermore, the Applicant has also disclosed that the FOXP3 polypeptide may comprise a deletion of amino acid positions 72-106 relative to SEQ ID NO. 1 (e.g. see page 20, lines 30-32). Alternatively, the FOXP3 polypeptide may comprise a deletion of amino acid positions 246-272 relative to SEQ ID NO. 1 (e.g. see page 20, lines 30-32).
The Applicant has also disclosed that the FOXP3 polypeptide comprises SEQ ID NO. 6 (e.g. see page 20, lines 34 and 35). The FOXP3 polypeptide may also comprise a deletion of amino acid positions 72-106 relative to SEQ ID NO. 6 or a deletion of amino acid positions 246-272 relative to SEQ ID NO. 6 (e.g. see page 21, lines 9-11).
Therefore, the Applicant has disclosed 10 species of FOXP3 polypeptides or functional fragments thereof: SEQ ID NOs: 1-6,
∆
72-106 of SEQ ID NO: 1,
∆
72-106 of SEQ ID NO: 6,
∆
246-272 of SEQ ID NO: 1, and
∆
246-272 of SEQ ID NO: 6.
Independent claims 1, 19, and 36 recite that the polynucleotide encodes a FOXP3 polypeptide.
Dependent claims 3 and 20 recite that the FOXP3 polypeptide comprises an amino acid sequence which is at least 80% identical to SEQ ID NO. 1 or a functional fragment thereof.
It is noted that the FOXP3 polypeptides of the instant invention, specifically claims 3 and 20, are defined broadly to encompass any FOXP3 polypeptide with a sequence that has at least two consecutive amino acids of SEQ ID NO: 1.
When given the broadest reasonable interpretation in light of specification, the FOXP3 polypeptide of the instant invention is defined broadly to be any FOXP3 polypeptide, any FOXP3 polypeptide comprising any two or more consecutive amino acids of SEQ ID NO: 1, or any functional fragment of any FOXP3 polypeptide.
It is noted that none of the claims indicate sufficient structure for the genus of FOXP3 polypeptides or subgenera comprising an amino acid sequence which is at least 80% identical to SEQ ID NO. 1 or a functional fragment thereof as claimed.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3). In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
Lopes et al. 2006 (J. Immunol. 177(5), 3133-3142, an IDS reference filed 08/09/2023) teach FOXP3 is a critical regulator of Treg development and function (e.g. see page 3140, right column, second paragraph). FOXP3 localizes to the nucleus and functions as a repressor of transcription from both a constitutively active promoter (SV40) and a promoter that is inducibly activated by the transcription factor NF-AT (IL-2) (e.g. see page 3140, right column, third paragraph). Both its nuclear localization and its repressor functions were found to be dependent on the presence of the FKH domain, because a mutant protein lacking the FKH domain did not localize to the nucleus and did not repress transcription. Furthermore, its DNA-binding ability is dependent on its FKH domain. FOXP3 contains at least two domains required for repressor function, and that these domains lie within the first 198 aa of FOXP3. The domain required for repression of the constitutively active SV40 promoter was localized to a region between aa 67 and 132 (e.g. see page 3140, right column, third paragraph). A Gal4-FOXP3 fusion protein consisting of aa 67–132 is not sufficient to repress NF-AT-mediated transcriptional activity (e.g. see paragraph spanning pages 3140 and 3141).
Lopes et al. also teach that other viral functions of FOXP3 include homodimerization and nuclear import (e.g. see page 3141, left column, second paragraph). FOXP3 forms homodimers which is dependent on the leucine zipper, because deletion of a conserved glutamic acid residue (ΔE251) in the leucine zipper inhibits dimerization. In addition, this mutation abrogated the repressor function of FOXP3. In contrast, a mutation that destroys the structure of the zinc finger did not affect dimerization or repressor function (e.g. see page 3141, left column, second paragraph).
Lopes et al. also teach two regions that are involved in nuclear localization and demonstrate that nuclear localization of FOXP3 is required for transcriptional repression (e.g. see page 3141, left column, third paragraph). A putative nuclear localization signal (NLS) at the carboxyl end of the FKH domain appears to act as the primary targeting sequence, but a point mutation at the amino end of the FKH domain (R347H, identified in a patient with IPEX) has a partial effect on nuclear targeting and completely abrogates repression of IL-2 transcription (e.g. see page 3141, left column, third paragraph).
Ultimately, Lopes et al. teach that loss of the FKH domain altogether, point mutations within the FKH domain, such as R347H, and mutation of a conserved glutamic acid residue within the leucine zipper (ΔE251), which inhibits homodimerization of FOXP3, lead to loss of repressor activity of FOXP3.
Song et al. 2012 (Cell Reports 1, 665–675, an IDS reference filed 08/09/2023) teach the deletion mutants, DelK250 and DelE251, of FOXP3 disrupt the homodimerization of FOXP3 and lead to impaired ability to repress transcription (e.g. see page 671, right column, last paragraph). Song et al. also teach that the FOXP3 L242P mutation is expected to directly alter the coiled-coil conformation and stability, and therefore affect the regulatory function of the FOXP3 homodimer (e.g. see page 672, paragraph spanning left and right columns).
Thus, based upon the art, skilled artisans would reasonably understand that in order for a FOXP3 polypeptide to be functional it requires the entire wildtype FKH domain and amino acid residues K250, E251, L242. This applies to the instant invention which is drawn to a genus of FOXP3 polypeptides which encompass any FOXP3 polypeptide and subgenera which are drawn to FOXP3 polypeptides that comprise as little as two consecutive amino acids from SEQ ID NO: 1 or any functional fragment thereof.
As noted above, the Applicant has disclosed 10 species of FOXP3 polypeptides or functional fragments thereof: SEQ ID NOs: 1-6,
∆
72-106 of SEQ ID NO: 1,
∆
72-106 of SEQ ID NO: 6,
∆
246-272 of SEQ ID NO: 1, and
∆
246-272 of SEQ ID NO: 6. SEQ ID NO: 1 represents full-length FOXP3, SEQ ID NOs: 2-4 represent S418E, S422A, and S418E and S422A mutants, respectively, SEQ ID NO: 5 represents an N and C terminally truncated FOXP3 fragment, and SEQ ID NO: 6 represents an illustrative variant of FOXP3 that comprises a deletion of residues 245-249 and 427-431 and a K252E point mutation.
Such a disclosure does not serve to provide sufficient written description of the claimed genus of FOXP3 polypeptides or subgenera comprising an amino acid sequence which is at least 80% identical to SEQ ID NO. 1 or a functional fragment thereof. Further, the disclosure does not identify any specific structural features or combination of features which give rise to the function of binding FOXP3 target DNA and acting as a transcription factor regulating development and function of Tregs. Additionally, there does not appear to be any reasonable shared structure present in the genus of recited FOXP3 polypeptides or subgenera comprising an amino acid sequence which is at least 80% identical to SEQ ID NO. 1 or a functional fragment thereof which gives rise to their functional activity. Ultimately, identifying a FOXP3 polypeptide simply on the basis of binding FOXP3 target DNA and acting as a transcription factor regulating development and function of Tregs rather than by identifying the sequence/structure, namely the entire amino acid sequence, of the FOXP3 polypeptides in question is generally insufficient to provide written description.
Ultimately, there is insufficient written description for the breadth of FOXP3 polypeptides as currently claimed. Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of FOXP3 polypeptides encompassed by the claims at the time the instant application was filed.
This reasoning further applies to claims 3 and 20 which recite the limitation that “the FOXP3 polypeptide comprises an amino acid sequence which is at least 80% identical to SEQ ID NO. 1.” Given the broadest reasonable interpretation, the FOXP3 polypeptide of instant claims 3 and 20 is defined broadly to be any FOXP3 polypeptide that comprises any amino acid sequence comprising two or more consecutive amino acids of SEQ ID NO: 1 with at least 80% sequence identity. Claims 3 and 20 do not satisfy the written description requirement because the claim language allows for FOXP3 polypeptides that do not comprise the entire wildtype FKH domain or amino acid residues K250, E251, and L242, which are required for a functional FOXP3 polypeptide based on the state of the art. Claims 3 and 20 are drawn to broad subgenera of FOXP3 polypeptide structures which are functionally defined by their ability to bind a FOXP3 target DNA and act as a transcription factor regulating development and function of Tregs without reciting a corresponding structure expected to correlate with this ability as supported by Applicant’s disclosure.
Amending the claims to recite that the FOXP3 polypeptide comprises the amino acid sequence of one of SEQ ID NOs: 1-6,
∆
72-106 of SEQ ID NO: 1,
∆
72-106 of SEQ ID NO: 6,
∆
246-272 of SEQ ID NO: 1, or
∆
246-272 of SEQ ID NO: 6 would obviate this part of the rejection.
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.
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.
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.
Claims 1-3, 6, 7, 9-11, 13, 15, 19, 20, 22-24, 26, 27, and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Stauss et al. 2019 (WO2019202323, an IDS reference filed 08/09/2023) in view of Gołąb et al. 2018 (Oncotarget. 9(11), 9728-9740, an IDS reference filed 08/09/2023).
Independent claim 1 is drawn to a method of preserving CD62L expression in a regulatory T cell (Treg) population that has been cryopreserved, comprising introducing a polynucleotide encoding a FOXP3 polypeptide into the Treg population prior to cryopreservation.
Dependent claim 2 limits the method to that wherein the Treg population has higher CD62L expression after cryopreservation than a corresponding non-engineered Treg population after cryopreservation.
Dependent claim 3 limits the method to that wherein: (a) the FOXP3 polypeptide comprises an amino acid sequence which is at least 80% identical to SEQ ID NO. 1 or a functional fragment thereof; (b) the polynucleotide encoding FOXP3 is within an expression vector; and/or (c) the method further comprises introducing a polynucleotide encoding an exogenous T cell receptor (TCR) or a polynucleotide encoding a chimeric antigen receptor (CAR) into the Treg population.
Dependent claim 6 limits the method of claim 3 to that wherein in part (c): (i) the polynucleotide encoding the FOXP3 polypeptide and the polynucleotide encoding the exogenous TCR or CAR are provided by a single expression vector, and/or (ii) there is an internal self-cleaving sequence between the polynucleotide encoding FOXP3 and the polynucleotide encoding the exogenous TCR or CAR.
Dependent claim 7 limits the method of claim 6 to that wherein the vector comprises a first polynucleotide encoding the FOXP3 polypeptide and a second polynucleotide encoding the exogenous TCR or CAR, wherein the first polynucleotide and the second polynucleotide are operably linked to the same promoter, and wherein the first polynucleotide is upstream of the second polynucleotide.
Dependent claim 9 limits the method to that wherein the polynucleotides encoding FOXP3 and/or the exogenous TCR or CAR are introduced into the Treg population by viral transduction, preferably retroviral or lentiviral transduction.
Dependent claim 10 limits the method to that further comprising the steps of (a) introducing a polynucleotide encoding a FOXP3 polypeptide into the Treg population; and (b) cryopreserving said Treg population.
Dependent claim 11 limits the method of claim 10 to that further comprising a step of: isolating a Treg population from a sample prior to introducing the polynucleotide encoding a FOXP3 polypeptide into said Treg population; and/or thawing said Treg population after cryopreservation.
Dependent claim 13 limits the method of claim 10 to that wherein: (A) step (b) comprises the following steps of:(bi) suspending said Treg population in a cryopreservation media; (bii) freezing the Treg population of (bi); and (biii) storing the Treg population of (bii) at a temperature below -130°C; and/or (B) the method further comprises the steps of: pre-chilling said Treg population, and/or any one or more reagents and devices to be used in the cryopreservation step, prior to step (b); cryopreserving said Treg population according to step (b) at a controlled rate of freezing of approximately -1 °C per minute; and/or storing the Treg population at -80°C for up to 24 hours prior to step (biii).
Dependent claim 15 limits the method of claim 11 to that wherein (a) thawing the Treg population comprises warming the Treg population from a temperature below -130°C to a temperature of between approximately 0-10°C, optionally wherein warming the Treg population comprises placing the Treg population in a water bath maintained at approximately 37°C; (b) the Treg population is isolated by selecting for: :(i) CD4+CD25+CD127- and/or CD4+CD25+CD127low cells; or (ii) CD4+CD25hiCD127- and/or CD4+CD25+CD127 low cells; and/or (c) the Treg population is isolated by selecting for CD45RA+ cells.
Independent claim 19 is drawn to a cryopreserved engineered Treg population comprising an exogenous polynucleotide encoding a FOXP3 polypeptide, wherein the engineered Treg population has higher CD62L expression after cryopreservation than a corresponding non-engineered Treg population after cryopreservation.
Dependent claim 20 limits the cryopreserved engineered Treg population to that wherein: (a)the FOXP3 polypeptide comprises an amino acid sequence which is at least 80% identical to SEQ ID NO. 1 or a functional fragment thereof; and/or (b) the exogenous polynucleotide encoding FOXP3 is within an expression vector.
Dependent claim 22 limits the cryopreserved engineered Treg population to that further comprising a polynucleotide encoding an exogenous T cell receptor (TCR) or a polynucleotide encoding a chimeric antigen receptor (CAR).
Dependent claim 23 limits the cryopreserved engineered Treg population of claim 22 to that wherein (a) the polynucleotide encoding the FOXP3 polypeptide and the polynucleotide encoding the exogenous TCR or the CAR are provided by a single expression vector; and/or (b) there is an internal self-cleaving sequence between the polynucleotide encoding FOXP3 and the polynucleotide encoding the exogenous TCR or CAR.
Dependent claim 24 limits the cryopreserved engineered Treg population of claim 23 to that wherein the vector comprises a first polynucleotide encoding the FOXP3 polypeptide and a second polynucleotide encoding the exogenous TCR or CAR, wherein the first polynucleotide and the second polynucleotide are operably linked to the same promoter, and wherein the first polynucleotide is upstream of the second polynucleotide.
Dependent claim 26 is drawn to a Treg population obtainable according to the method of claim 1.
Dependent claim 27 is drawn to a pharmaceutical composition comprising a Treg population according to claim 19.
Independent claim 36 is drawn to a method for producing a cryopreserved Treg or population of Tregs having a level of CD62L comparable to a corresponding non-cryopreserved Treg or population of Tregs comprising (a) introducing a polynucleotide encoding FOXP3 into a Treg or population of Tregs and (b) cryopreserving said Treg or population of Tregs.
Regarding claims 1, 2, 10, 19, 26, and 36, Stauss et al. teach a method for improving the immunosuppressive ability of Treg cells by introducing a polynucleotide expressing FOXP3 into the Tregs (e.g. see claim 1). Regarding claims 3 and 22, the Tregs can be further transduced with a TCR construct or a CAR construct (e.g. see claim 4). Further regarding claim 3 and regarding claims 6, 7, 20, 23, and 24, these polynucleotides may be expressed from one expression vector, wherein the vector comprises a nucleic acid with the orientation: 5’ FOXP3 - X - TCR/CAR 3’; wherein X is an internal self-cleaving sequence (e.g. see claims 5 and 6).
Further regarding claims 3 and 20, Stauss et al. also teach that the FOXP3 polypeptide comprises an amino acid sequence which is at least 80 % identical to SEQ ID NO: 3 or 4 or a functional fragment thereof (e.g. see claim 2). It is noted that SEQ ID NO: 3 is identical to instant SEQ ID NO: 1 and SEQ ID NO: 4 shares at least 80% sequence identity with instant SEQ ID NO: 1. See sequence alignments below.
Regarding claims 9 and 11, Stauss et al. also teach that the polynucleotide encoding FOXP3 is introduced into the isolated Treg by viral transduction; optionally wherein the polynucleotide encoding FOXP3 is introduced into the isolated Treg by retroviral transduction. Further regarding claim 11, Stauss et al. also teach that the Tregs were isolated prior to introducing the polynucleotide encoding the FOXP3 polypeptide into said Treg population (e.g. see Examples 1A and 1B, page 29, line 28 – page 30, line 17). Example 1A details the isolation of the Tregs prior to the transduction of the isolated Tregs with FOXP3 in example 1B.
Regarding claim 15, Stauss et al. also teach that the Treg is isolated by selecting for (i) CD4+CD25+CD127- and/or CD4+CD25+CD127low cells; or (ii) CD4+CD25hiCD127- and/or CD4+CD25+CD127 low cells (e.g. see claim 12). Further regarding claim 15, Stauss et al. also teach that the Treg may be a CD45RA+ Treg (e.g. see page 6, line 29, and page 30, line 1).
Regarding claim 27, Stauss et al. also teach a pharmaceutical composition comprising the engineered Treg (e.g. see claim 21).
Alignment of Stauss et al.’s SEQ ID NO: 3 and instant SEQ ID NO: 1:
Query Match 100.0%; Score 2312; DB 1; Length 431;
Best Local Similarity 100.0%;
Matches 431; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MPNPRPGKPSAPSLALGPSPGASPSWRAAPKASDLLGARGPGGTFQGRDLRGGAHASSSS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MPNPRPGKPSAPSLALGPSPGASPSWRAAPKASDLLGARGPGGTFQGRDLRGGAHASSSS 60
Qy 61 LNPMPPSQLQLPTLPLVMVAPSGARLGPLPHLQALLQDRPHFMHQLSTVDAHARTPVLQV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 LNPMPPSQLQLPTLPLVMVAPSGARLGPLPHLQALLQDRPHFMHQLSTVDAHARTPVLQV 120
Qy 121 HPLESPAMISLTPPTTATGVFSLKARPGLPPGINVASLEWVSREPALLCTFPNPSAPRKD 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 HPLESPAMISLTPPTTATGVFSLKARPGLPPGINVASLEWVSREPALLCTFPNPSAPRKD 180
Qy 181 STLSAVPQSSYPLLANGVCKWPGCEKVFEEPEDFLKHCQADHLLDEKGRAQCLLQREMVQ 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 STLSAVPQSSYPLLANGVCKWPGCEKVFEEPEDFLKHCQADHLLDEKGRAQCLLQREMVQ 240
Qy 241 SLEQQLVLEKEKLSAMQAHLAGKMALTKASSVASSDKGSCCIVAAGSQGPVVPAWSGPRE 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 SLEQQLVLEKEKLSAMQAHLAGKMALTKASSVASSDKGSCCIVAAGSQGPVVPAWSGPRE 300
Qy 301 APDSLFAVRRHLWGSHGNSTFPEFLHNMDYFKFHNMRPPFTYATLIRWAILEAPEKQRTL 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 APDSLFAVRRHLWGSHGNSTFPEFLHNMDYFKFHNMRPPFTYATLIRWAILEAPEKQRTL 360
Qy 361 NEIYHWFTRMFAFFRNHPATWKNAIRHNLSLHKCFVRVESEKGAVWTVDELEFRKKRSQR 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 NEIYHWFTRMFAFFRNHPATWKNAIRHNLSLHKCFVRVESEKGAVWTVDELEFRKKRSQR 420
Qy 421 PSRCSNPTPGP 431
|||||||||||
Db 421 PSRCSNPTPGP 431
Alignment of Stauss et al.’s SEQ ID NO: 4 and instant SEQ ID NO: 1:
Query Match 95.7%; Score 2266.5; DB 1; Length 431;
Best Local Similarity 98.4%;
Matches 424; Conservative 1; Mismatches 1; Indels 5; Gaps 1;
Qy 1 MPNPRPGKPSAPSLALGPSPGASPSWRAAPKASDLLGARGPGGTFQGRDLRGGAHASSSS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MPNPRPGKPSAPSLALGPSPGASPSWRAAPKASDLLGARGPGGTFQGRDLRGGAHASSSS 60
Qy 61 LNPMPPSQLQLPTLPLVMVAPSGARLGPLPHLQALLQDRPHFMHQLSTVDAHARTPVLQV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 LNPMPPSQLQLPTLPLVMVAPSGARLGPLPHLQALLQDRPHFMHQLSTVDAHARTPVLQV 120
Qy 121 HPLESPAMISLTPPTTATGVFSLKARPGLPPGINVASLEWVSREPALLCTFPNPSAPRKD 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 HPLESPAMISLTPPTTATGVFSLKARPGLPPGINVASLEWVSREPALLCTFPNPSAPRKD 180
Qy 181 STLSAVPQSSYPLLANGVCKWPGCEKVFEEPEDFLKHCQADHLLDEKGRAQCLLQREMVQ 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 STLSAVPQSSYPLLANGVCKWPGCEKVFEEPEDFLKHCQADHLLDEKGRAQCLLQREMVQ 240
Qy 241 SLEQ-----VEELSAMQAHLAGKMALTKASSVASSDKGSCCIVAAGSQGPVVPAWSGPRE 295
|||| |:||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 SLEQQLVLEKEKLSAMQAHLAGKMALTKASSVASSDKGSCCIVAAGSQGPVVPAWSGPRE 300
Qy 296 APDSLFAVRRHLWGSHGNSTFPEFLHNMDYFKFHNMRPPFTYATLIRWAILEAPEKQRTL 355
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 APDSLFAVRRHLWGSHGNSTFPEFLHNMDYFKFHNMRPPFTYATLIRWAILEAPEKQRTL 360
Qy 356 NEIYHWFTRMFAFFRNHPATWKNAIRHNLSLHKCFVRVESEKGAVWTVDELEFRKKRSQR 415
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 NEIYHWFTRMFAFFRNHPATWKNAIRHNLSLHKCFVRVESEKGAVWTVDELEFRKKRSQR 420
Qy 416 PSRCSNPTPGP 426
|||||||||||
Db 421 PSRCSNPTPGP 431
Regarding the preamble of claim 1 which recites “A method of preserving CD62L expression in a regulatory T cell (Treg) population that has been cryopreserved”; it is noted that if the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction (see MPEP 2111.02.II). This applies to the instant case wherein the only active step of claim 1 is the introduction of “a polynucleotide encoding a FOXP3 polypeptide into the Treg population prior to cryopreservation” in lines 2 and 3. Therefore, given that this step (limitation) does not recite the preservation of CD62L expression, the preamble has not been considered a limitation for the purpose of applying prior art.
Nonetheless, regarding the results/properties of “preserving CD62L expression in a regulatory T cell (Treg) population” (claim 1), “wherein the (engineered) Treg population has higher CD62L expression after cryopreservation than a corresponding non-engineered Treg population after cryopreservation” (claims 2 and 19), and “a cryopreserved Treg or population of Tregs having a level of CD62L comparable to a corresponding non-cryopreserved Treg or population of Tregs” (claim 36), Stauss et al. is silent on these results/properties. However, silence about a particular result/property does not necessarily constitute its absence. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that there is a difference between the methods/materials, i.e., that the claims are directed to new methods/materials, and that such a difference would have been considered unexpected by one of ordinary skill in the art, that is, the claimed subject matter, if new, is unobvious.
In the absence of evidence to the contrary, the burden is on the Applicant to prove that the claimed methods/materials are different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Although Stauss et al. is silent with regard to the expression of CD62L on the Treg cells, it is noted that a method/compound and all of its properties are inseparable; they are one and the same thing (see In re Papesch, CCPA 137 USPQ 43; In re Swinehart and Sfiligoj, 169) USPQ 226 (CCPA 1971)). Therefore, in the absence of evidence to the contrary, the method of improving the immunosuppressive ability of Treg cells by introducing a polynucleotide expressing FOXP3 into the Tregs taught by Stauss et al. would have the claimed results as recited in claims 1, 2, 19, and 36.
When a claim recites using an old method/material (e.g., introducing a polynucleotide expressing FOXP3 into Tregs/Tregs that express exogenous FOXP3) and the result is directed to a result or property of that method (results/properties recited in claims 1, 2, 19, and 36) then the claim is anticipated. See MPEP 2112.02. Also, see Bristol-Myers Squibb Co. v. Ben Venue Laboratories, Inc. 58 USPQ2d 1508 (CA FC 2001); Ex parte Novitski 26 USPQ 1389 (BPAI 1993); Mehl/Biophile International Corp. V. Milgraum, 52 USPQ2d 1303 (Fed. Cir. 1999); Atlas Powder Co. V. IRECO, 51 USPQ2d 1943 (Fed. Cir. 1999).
The Courts have held that there is no requirement that those of ordinary skill in the art know of the inherent result. See MPEP 2131.01(d) and MPEP 2112 - 2113.
Stauss et al. do not teach that the Treg cells are cryopreserved, that the cryopreservation comprises the steps of (bi) suspending said Treg population in a cryopreservation media; (bii) freezing the Treg population of (bi); and (biii) storing the Treg population of (bii) at a temperature below -130°C, or that the Treg cells are thawed after cryopreservation.
Gołąb et al. teach that from a logistical perspective, it would be much more convenient if pure Tregs or other cells containing Tregs could be stored in sufficient quantity, allowing Tregs to be applied at an optimal time without prolonged processing (e.g. see page 9729, left column, second paragraph). Therefore banking of cryopreserved Treg cells that are ready to be used is critically important (e.g. see page 9729, left column, second paragraph).
Gołąb et al. also teach that the steps of cryopreservation included that the Tregs were (1) suspended in cryoprotectant solution (or media), (2) frozen to -90°C, and (3) stored at –196°C (e.g. see page 9736, left column, third paragraph). Gołąb et al. also teach that the Treg cells were thawed after cryopreservation (e.g. see page 9736, right column, second paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Stauss et al. to incorporate the teachings of Gołąb et al. to include that the Treg cells are cryopreserved, that the cryopreservation comprises the steps of (bi) suspending said Treg population in a cryopreservation media; (bii) freezing the Treg population of (bi); and (biii) storing the Treg population of (bii) at a temperature below -130°C, and that the Treg cells are thawed after cryopreservation. This is because banking of cryopreserved Treg cells that are ready to be used is critically important.
Given that introducing a polynucleotide expressing FOXP3 into the Tregs is meant to improve their immunosuppressive ability, the need for Tregs that are stored in sufficient quantity to allow them to be applied at an optimal time without prolonged processing, and the importance of banking cryopreserved Treg cells that are ready to be used; it would have been obvious to a skilled artisan to cryopreserve the Treg cells taught by Stauss et al. with a reasonable expectation of success. It is routine practice to cryopreserve Treg cells for later use and a skilled artisan, with the intent us applying Stauss et al.’s FOXP3 engineered Treg cells later on, would reasonably choose to cryopreserve the engineered Treg cells according to the method taught by Gołąb et al. and, once ready to use them, thaw them after cryopreservation.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
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/GRACE H LUNDE/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641