DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 January 8, 2026 has been entered. Any prior objection or rejection that is not repeated or addressed below is either moot or withdrawn in view of Applicant’s amendment.
Claims Summary
Claims 1, 20, 30, 32, 35, 39, 42, 47 and 79
Claim 1 is directed to a pharmaceutical formulation comprising:
Activating Antigen Carriers (AACs) that comprise at least one antigen and an adjuvant; the antigen comprises one or more HPV antigens, SEQ ID NO: 19 and 23 (elected species) (claims 35 and 39); the adjuvant comprises CpG, among others (claim 42); and
DMSO cryopreservation medium (claim 1)
Post-thawing, the formulation comprises about 0.5x106 to about 1.0x106 AACs/mL, among other values recited in claim 1. The amount of AACs in the formulation comprises about 0.5x109 to about 1x1010, or about 0.5x109 to about 1x109 AACs/mL, or about 7.0x109 in about 9.5 mL of cryopreservation medium wherein the pH is about 7.6 (claim 30). The formulation has a pH of about 6.0 to about 8.5 (claim 20). The formulation is sterile, comprises less than about 2 EU/mL endotoxin, is free of mycoplasma, or any combination of the foregoing (claim 32). Also claimed is a vial comprising the formulation (claim 47). New claim 79 is directed to an embodiment wherein the AACs are not chemically treated.
Claims 10, 16, 22, 23 and 80
Claim 10 is directed to a pharmaceutical formulation comprising:
AACs that comprise at least one antigen and an adjuvant; at least about 70% of the AACs are positive for annexin staining (claim 10); and
A cryopreservation medium, specifically DMSO (claim 16)
Post-thawing, the formulation comprises about 0.5x106 to about 1.0x106 AACs/mL, among other values recited in claims 22 and 23. The amount of AACs in the formulation comprises about 0.5x109 to about 1x1010, or about 0.5x109 to about 1x109 AACs/mL, wherein the pH of the formulation is about pH 6.0 to about pH 8.5 (claim 22). In another embodiment the amount of AACs in the formulation comprises about 0.5x109 to about 1x1010 AACs, or about 0.5x109 to about 1x109 AACs/mL in the cryopreservation medium, wherein the pH of the formulation is about pH 7.6 (claim 23). New claim 80 is directed to an embodiment wherein the AACs are not chemically treated.
Claims 60-62, 66 and 75
Claim 60 is directed to a method of producing a pharmaceutical formulation comprising AACs that comprise at least one antigen and an adjuvant, comprising adding a cryopreservation medium to the AACs. More specifically, the method comprises freezing the formulation, the freezing comprising:
Reducing the temperature of a chamber comprising the formulation of AACs to between about 0°C and -20°C, preferably about -3°C;
Reducing the temperature of the chamber to about -140°C +/- 5°C at a rate of between about -10°C per minute about -30°C per minute, preferably about -20°C per minute;
Reducing the temperature of the chamber to about -150°C +/- 5°C at a rate of between about -0.5°C per minute and -5°C per minute, preferably about -1.5°C per minute;
Reducing the temperature of the chamber to about -170°C +/- 5°C at a rate of between about -0.1°C per minute and -5°C per minute, preferably -1.0°C per minute; and
Holding the temperature of the chamber at about -170°C +/- 5°C for at least about 5 to 30 minutes, preferably about 10 minutes.
In claim 61, the method further comprises:
Passing a cell suspension comprising input anucleate cells (RBCs, claim 75) through a cell-deforming constriction, thereby causing perturbations of the cells; and
Contacting the perturbed cells with the at least one antigen and the adjuvant such that they enter the cells, generating the AACs.
The diameter of the constriction is about 1.6 µm to about 2.4 µm (claim 62). About 1x109 to about 1x1010 AACs are formulated in about 9 mL to about 10 mL of the cryopreservation medium (claim 66).
Claim Objections
(New Objection) Claims 1, 10, 16, 20, 22, 23, 30, 32, 35, 39, 42, 47, 60, 66, 79 and 80 are objected to because of the following informalities:
With regard to claims 1, 10 and dependent claims 16, 20, 22, 23, 30, 32, 35, 39, 42, 47, 60, 66, 79 and 80, while it may be implied that there is a carrier element in the “activating antigen carriers”, the claims do not recite any element that represents a “carrier”. (The antigen and adjuvant do not appear to represent a carrier.) While it may also be implied that cells are the carrier (because of the presence of DMSO which is used for cryopreservation of cells, as well as the recitation of concentrations of AACs/mL), the claims do not explicitly recite the presence of cells. Clarification and/or correction is required. It is noted that the only cells contemplated for the invention appear to be anucleate cells.
With regard to claims 79 and 80, the claims are directed to “The method of claim 1” and “The method of claim 22”, respectively, however, claims 1 and 22 are product claims. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
(New Rejection) Claims 79 and 80 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.
New claims 79 and 80 are directed to embodiments wherein the AACs are not chemically treated. The specification at paragraph [0169] of the published application (US 20220233676) discloses input anucleate cells that are not chemically treated during the preparation of the anucleate cell-derived vesicles. However, the AACs of claims 79 and 80 are in a composition comprising DMSO, which is a chemical. Thus, it is not clear how the AACs are not chemically treated when they are present in a composition comprising DMSO. The metes and bounds of the chemical treatment cannot be determined.
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.
(New Rejection) Claims 79 and 80 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for 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. This is a new matter rejection.
New claims 79 and 80 are directed to embodiments wherein the AACs are not chemically treated. The specification at paragraph [0169] of the published application (US 20220233676) discloses input anucleate cells that are not chemically treated during the preparation of the anucleate cell-derived vesicles. However, claims 79 and 80 are not limited to anucleate cells. While anucleate cells are disclosed in the specification as AACs (see paragraph [0112] of the published application) AACs are not limited to anucleate cells.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 20, 30, 32, 35 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Ditommaso et al. (US 2019/0017072 A1, “Ditommaso”) in view of McGann et al. (US 2006/0063141 A1, “McGann”) and Crowe et al. (US 2002/0114791 A1, “Crowe”). The claims are summarized above and correlated with the teachings of the prior art in bold font below.
Ditommaso discloses delivery of a complex of antigen, such as HPV16 E7 synthetic long peptide, associated with an adjuvant (see paragraphs [0080], [0082]) to a cell (claim 1, aspect of AACs; claim 35). Compositions comprising pharmaceutically acceptable carriers are contemplated, as well as administration of the cells, and vials (see paragraphs [0036], [0126] and [0129]) (claim 1, aspect of pharmaceutical formulation; claim 47). The pH at which the complex is contacted with the cells is between about 5.5 to about 8.5 (see paragraph [0010]) (claims 20 and 30).
Ditommaso does not suggest cryopreserving cells. However, it would have been obvious to have done so with a reasonable expectation of success, motivated by the convenience of preserving cells for future use, as seen in McGann (see paragraphs [0003] and [0021]). McGann discloses methods of cryopreserving cells, including RBCs, using a non-linear cooling method with DMSO in solution (see abstract, paragraphs [0003], [0009], [0014], [0015], [0111] and [0128]) (claim 1).
Ditommaso does not teach sterile compositions, however, suggest cryopreserving cells. However, it would have been obvious to have produced a sterile composition in order to reduce the risk of contamination, with a reasonable expectation of success, as in Crowe. Crowe discloses preserving cells for future use (see paragraphs [0003] and [0005]), and Crowe’s pharmaceutical compositions are sterile (see paragraph [0121]) (claim 32).
Ditommaso does not disclose AAC concentrations, nor the post-thaw AAC concentrations, as in claims 1 and 30, however, Crowe discloses a method of cryopreservation of RBCs by loading cryopreservation medium to the RBCs (see paragraph [0017], for example), wherein the cell concentration is anywhere from about 105 to 1010, 106 to 109, and 107 to 108 per ml of medium (see paragraphs [0139] and [0150]). While the particular values of 0.5x109 and 7x109 in about 9.5 ml, respectively, are not disclosed, such values would have been the result of routine optimization given that the amount of cells in relation to the amount of cryopreservation medium would result in varying degrees of viable cells recovered, which is a result-effective variable. Further, the use of the term “about” to describe the amounts leaves room for the neighboring values disclosed by Crowe (outlined above). As for the post-thaw AAC concentrations, those values are a natural outcome of doing what the prior art suggests. Since the product of Ditommaso in view of McGann and Crowe is the same as Applicant’s product, any post-thaw concentrations would be a natural outcome. Therefore, the claimed embodiments would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Applicant’s remarks filed January 8, 2026 have been carefully considered but fail to persuade. Applicant argues that Crowe teaches that cell concentrations below 3x108 cells/mL results in around 70% recovery, while cell concentrations higher than that result in “very low values” of recovery, pointing to paragraph [0192] in Crowe. Applicant reasons that given this information, one would not have been motivated to formulate Ditomasso’s product having a cell concentration range as claimed (values from 109 to 1010 AACs/mL), which, according Crowe, would result in low recover because the cell concentration is higher than Crowe’s 3x108 cells/mL.
In response to Applicant’s argument, paragraph [0192] of Crowe is directed to platelets, not cells. Crowe discloses a method of cryopreservation of RBCs by loading cryopreservation medium to the RBCs (see paragraph [0017], for example), wherein the cell concentration is anywhere from about 105 to 1010, 106 to 109, and 107 to 108 per ml of medium (see paragraphs [0139] and [0150]).
Claim 39 is rejected under 35 U.S.C. 103 as being unpatentable over Ditommaso et al. (US 2019/0017072 A1, “Ditommaso”) in view of McGann et al. (US 2006/0063141 A1, “McGann”) and Crowe et al. (US 2002/0114791 A1, “Crowe”) as applied to claim 1 above, and further in view of Van Der Burg et al. (US Patent 9,562,075, “Van Der Berg”) and Loughhead et al. (WO 2019/178006 A2, published 9/19/2019, “Loughhead”). Claim 39 is directed to an embodiment wherein the HPV antigens comprise SEQ ID NO: 19 and SEQ ID NO: 23.
The teachings of Ditommaso and Crowe are outlined above. Ditommaso discloses the use of any antigen, such as viral antigens (e.g., HPV16 E7 synthetic long peptide) but does not provide the sequences set forth in Applicant’s SEQ ID NO: 19 and 23. It would have been obvious to have used any HPV sequences with a reasonable expectation of success, such as Loughhead’s HPV16 E7 protein fragment, SEQ ID NO: 23 (see paragraph [0361]), which is identical to Applicant’s SEQ ID NO: 23, and Van Der Burg’s HPV 16 E6 protein fragment, SEQ ID NO: 12, which is identical to Applicant’s SEQ ID NO: 19 (see col. 6, line 27). One would have been motivated to use multiple sequences from HPV in view of Van Der Burg’s suggestion to use antigens from E2, E6 and E7 in order to improve immunogenicity (see col. 5, lines 46-48). Therefore, the claimed embodiment would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. Applicant’s argument filed January 8, 2026 has been addressed above.
Claim 42 is rejected under 35 U.S.C. 103 as being unpatentable over Ditommaso et al. (US 2019/0017072 A1, “Ditommaso”) in view of McGann et al. (US 2006/0063141 A1, “McGann”) and Crowe et al. (US 2002/0114791 A1, “Crowe”) as applied to claim 1 above, and further in view of Sharei et al. (US 2018/0142198 A1, “Sharei”). Claim 42 is directed to an embodiment wherein the adjuvant is, for example, CpG, among others.
The teachings of Ditommaso, McGann and Crowe are outlined above. Ditommaso discloses delivery of a complex of antigen associated with an adjuvant (see paragraphs [0080], [0082]) to a cell, but does not identify any particular adjuvants. Given this general disclosure of an adjuvant, one would have been motivated to identify a particular adjuvant for use in the construct. It would have been obvious to have used CpG as the adjuvant in Ditommaso’s construct, with a reasonable expectation of success. Sharei discloses delivery of a payload, such as an antigen and/or adjuvant, including CpG, R848, LPS, etc., into immune cells via constriction of the cells (see paragraphs [0074]-[0079] and [0109]). One would have been motivated to use the adjuvants disclosed in Sharei as the adjuvant in Ditommaso’s construct, given Ditommaso’s generic disclosure of adjuvant, and given that the context of cell constriction/delivery of payloads into cells is shared by Sharei and Ditommaso. Therefore, the claimed embodiment would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. Applicant’s argument filed January 8, 2026 has been addressed above.
Claims 10 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Ditommaso et al. (US 2019/0017072 A1, “Ditommaso”) in view of McGann et al. (US 2006/0063141 A1, “McGann”) and Boersma et al. (J Nucl Med, 2005, 46:2035-2050, “Boersma”). The claims are summarized above and correlated with the teachings of the prior art in bold font below.
Ditommaso discloses delivery of a complex of antigen, such as HPV16 E7 synthetic long peptide, associated with an adjuvant (see paragraphs [0080], [0082]) to a cell (claim 10, aspect of AACs). Compositions comprising pharmaceutically acceptable carriers are contemplated, as well as administration of the cells, and vials (see paragraphs [0036], [0126] and [0129]) (claim 10, aspect of pharmaceutical formulation).
Ditommaso’s method comprises constriction of cells, such as RBCs, causing perturbations that allow the complex to enter the cells, such as through a pore of a membrane (see paragraphs [0005], [0031] and [0093]). Ditommaso does not disclose the number of cells that undergo constriction and perturbation, however, it would have been obvious to have used annexin binding to determine the number of cells that receive the complex (i.e., successful production of AACs). Boersma discloses annexin A5 as a diagnostic tool that binds to phosphatidylserine, a marker for apoptotic cells (see abstract). In viable cells, phosphatidylserine is present on the inner side of the cell membrane (see Boersma, page 2036, left column, last full paragraph, second sentence). One would have been motivated to use annexin binding to exposed phosphatidylserine of the cell membrane to determine how many cells in Ditommaso’s method receive the complex through constriction and perturbation, with a reasonable expectation of success. Given that the method is expected to constrict and perturb every cell, at least about 70% of the AACs would be expected to stain positive for annexin (claim 10).
Ditommaso does not suggest cryopreserving cells. However, it would have been obvious to have done so with a reasonable expectation of success, motivated by the convenience of preserving cells for future use, as seen in McGann (see paragraphs [0003] and [0021]). McGann discloses methods of cryopreserving cells, including RBCs, using a non-linear cooling method with DMSO in solution (see abstract, paragraphs [0003], [0009], [0014], [0015], [0111] and [0128]) (claim 16). Therefore, the claimed embodiments would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Applicant’s remarks filed January 8, 2026 have been carefully considered but fail to persuade. Applicant argues that, based on the examiner’s reasoning above, one would not have expected that at least about 70% of AACs modified through construction and perturbation would stain positive for annexin, since Ditommaso’s Figure 6D shows cell viabilities of about 80% post-modification. Applicant reasons that since annexin is a marker of apoptotic cells, and 80% of Ditomasso’s cells were viable, one would not have expected that at least about 70% of Ditommaso’s cells would stain positive for annexin.
In response, Ditommaso’s method comprises constriction of cells causing perturbations that allow the complex to enter the cells through, for example, a pore of a membrane (see paragraphs [0031]). In viable cells, phosphatidylserine is present on the inner side of the cell membrane (see Boersma, page 2036, left column, last full paragraph, second sentence). One would have been motivated to use annexin binding to exposed phosphatidylserine of the cell membrane, to determine how many cells in Ditommaso’s method receive the complex through constriction and perturbation, with a reasonable expectation of success. Given that the method is expected to constrict and perturb every cell, at least about 70% of the AACs would be expected to stain positive for annexin. Therefore, the claims remain rejected.
Claims 22 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Ditommaso et al. (US 2019/0017072 A1, “Ditommaso”) in view of McGann et al. (US 2006/0063141 A1, “McGann”) and Boersma et al. (J Nucl Med, 2005, 46:2035-2050, “Boersma”) as applied to claim 10 above, and further in view of Crowe et al. (US 2002/0114791 A1, “Crowe”). Claims 22 and 23 are directed to embodiments of AAC concentration and pH.
The teachings of Ditommaso, McGann and Boersma are outlined above. Additionally, Ditommaso discloses the pH at which the complex is contacted with the cells to be between about 5.5 to about 8.5 (see paragraph [0010]) (claims 22 and 23, aspect of pH). Ditommaso does not disclose AAC concentrations, nor post-thaw AAC concentrations, however, Crowe discloses a method of cryopreservation of RBCs by loading cryopreservation medium to the RBCs (see paragraph [0017], for example), wherein the cell concentration is anywhere from about 105 to 1010, 106 to 109, and 107 to 108 per ml of medium (see paragraphs [0139] and [0150]). While the particular value of 0.5x109 is not disclosed, it would have been the result of routine optimization given that the amount of cells in relation to the amount of cryopreservation medium would result in varying degrees of viable cells recovered, which is a result-effective variable. Further, the use of the term “about” to describe the amounts leaves room for the neighboring values disclosed by Crowe (outlined above). As for the post-thaw AAC concentrations, those values are a natural outcome of doing what the prior art suggests. Since the product of Ditommaso in view of McGann and Crowe is the same as Applicant’s product, any post-thaw concentrations would be a natural outcome. Therefore, the claimed embodiments would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. Applicant’s argument filed January 8, 2026 has been addressed above.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 32 and 42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 7, 44, 64, 75, 76, 81, 85, 86, 93, 113, 123, 152, 154, 161, 181, 221, 225 and 230 of copending Application No. 17/425,709 (reference application) in view of McGann et al. (US 2006/0063141 A1, “McGann”) and Crowe et al. (US 2002/0114791 A1, “Crowe”). Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims do not recite the embodiments of cryopreservation or cryopreservation media. However, it would have been obvious to have claimed such with a reasonable expectation of success, motivated by the convenience of preserving cells for future use, as seen in McGann (see paragraphs [0003] and [0021]). McGann discloses methods of cryopreserving cells, including RBCs, using a non-linear cooling method with DMSO in solution (see abstract, paragraphs [0003], [0009], [0014], [0015], [0111] and [0128]).
The copending claims do not disclose AAC concentrations, however, Crowe discloses a method of cryopreservation of RBCs by loading cryopreservation medium to the RBCs (see paragraph [0017], for example), wherein the cell concentration is anywhere from about 105 to 1010, 106 to 109, and 107 to 108 per ml of medium (see paragraphs [0139] and [0150]). While the particular value of 0.5x109 is not disclosed, it would have been the result of routine optimization given that the amount of cells in relation to the amount of cryopreservation medium would result in varying degrees of viable cells recovered, which is a result-effective variable. Further, the use of the term “about” to describe the amounts leaves room for the neighboring values disclosed by Crowe (outlined above). As for the post-thaw AAC concentrations, those values are a natural outcome of doing what the prior art suggests.
The copending claims are not directed to embodiments wherein the composition is sterile, however, Crowe’s pharmaceutical compositions are sterile (see paragraph [0121]). It would have been obvious to have claimed a sterile composition in order to reduce the risk of contamination, with a reasonable expectation of success. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Applicant’s arguments have been addressed above.
Claims 20, 30, 35 and 47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 7, 44, 64, 75, 76, 81, 85, 86, 93, 113, 123, 152, 154, 161, 181, 221, 225 and 230 of copending Application No. 17/425,709 (reference application) in view of McGann et al. (US 2006/0063141 A1, “McGann”) and Crowe et al. (US 2002/0114791 A1, “Crowe”), as applied to claim 1 above, and further in view of Ditommaso et al. (US 2019/0017072 A1, “Ditommaso”). Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claims 20 and 30 are directed to embodiments wherein the pH of the formulation is about 6.0 to about 8.5, or about 7.5. Instant claim 35 is directed to an embodiment wherein the antigen is an HPV antigen. Instant claim 47 is directed to an embodiment wherein the formulation is in a vial. These embodiments are not claimed in the copending application.
Instant claim 30 is directed to an embodiment wherein the AAC concentration is about 7x109 in about 9.5 ml, which is not claimed in the pending claims. However, such a value would have been the result of routine optimization given that the amount of cells in relation to the amount of cryopreservation medium would result in varying degrees of viable cells recovered, which is a result-effective variable.
Ditommaso discloses delivery of a complex of antigen, such as HPV16 E7 synthetic long peptide, associated with an adjuvant (see paragraphs [0080], [0082]) to a cell. The method comprises constriction of cells, such as RBCs, causing perturbations that allow the complex to enter the cells (see paragraphs [0005] and [0093]). Compositions comprising pharmaceutically acceptable carriers are contemplated, as well as administration of the cells, and vials (see paragraphs [0036], [0126] and [0129]). The pH at which the complex is contacted with the cells is between about 5.5 to about 8.5 (see paragraph [0010]). It would have been obvious to have incorporated these features into the copending claims with a reasonable expectation of success in view of the similar nature of Ditommaso’s compositions and methods. One would have been motivated to claim a pH range, a particular type of antigen, and a vial, as these specific embodiments further define a similar core product and method recited at a higher level of generality. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Applicant’s arguments have been addressed above.
Claim 39 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 7, 44, 64, 75, 76, 81, 85, 86, 93, 113, 123, 152, 154, 161, 181, 221, 225 and 230 of copending Application No. 17/425,709 (reference application) in view of McGann et al. (US 2006/0063141 A1, “McGann”) and Crowe et al. (US 2002/0114791 A1, “Crowe”) and Ditommaso et al. (US 2019/0017072 A1, “Ditommaso”), as applied to claim 35 above, and further in view of Van Der Burg et al. (US Patent 9,562,075, “Van Der Berg”) and Loughhead et al. (WO 2019/178006 A2, published 9/19/2019, “Loughhead”). Claim 39 is directed to an embodiment wherein the HPV antigens comprise SEQ ID NO: 19 and SEQ ID NO: 23. Although the claims at issue are not identical, they are not patentably distinct from each other.
Ditommaso discloses the use of any antigen, such as viral antigens (e.g., HPV16 E7 synthetic long peptide) but does not provide the sequences set forth in Applicant’s SEQ ID NO: 19 and 23. It would have been obvious to have claimed any HPV sequences with a reasonable expectation of success, such as Loughhead’s HPV16 E7 protein fragment, SEQ ID NO: 23 (see paragraph [0361]), which is identical to Applicant’s SEQ ID NO: 23, and Van Der Burg’s HPV 16 E6 protein fragment, SEQ ID NO: 12, which is identical to Applicant’s SEQ ID NO: 19 (see col. 6, line 27). One would have been motivated to use multiple sequences from HPV in view of Van Der Burg’s suggestion to use antigens from E2, E6 and E7 in order to improve immunogenicity (see col. 5, lines 46-48). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Applicant’s arguments have been addressed above.
Claims 10 and 16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 7, 44, 64, 75, 76, 81, 85, 86, 93, 113, 123, 152, 154, 161, 181, 221, 225 and 230 of copending Application No. 17/425,709 (reference application) in view of McGann et al. (US 2006/0063141 A1, “McGann”) and Boersma et al. (J Nucl Med, 2005, 46:2035-2050, “Boersma”). Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims do not recite the embodiments of cryopreservation or cryopreservation media. However, it would have been obvious to have claimed such with a reasonable expectation of success, motivated by the convenience of preserving cells for future use, as seen in McGann (see paragraphs [0003] and [0021]). McGann discloses methods of cryopreserving cells, including RBCs, using a non-linear cooling method with DMSO in solution (see abstract, paragraphs [0003], [0009], [0014], [0015], [0111] and [0128]).
The copending claims are not directed to the percentage of cells that stain positive for annexin. However, it would have been obvious to have claimed such as a result of using annexin binding to determine the number of cells that receive the complex (i.e., successful production of AACs). Boersma discloses annexin A5 as a diagnostic tool that binds to phosphatidylserine, a marker for apoptotic cells (see abstract). In viable cells, phosphatidylserine is present on the inner side of the cell membrane (see Boersma, page 2036, left column, last full paragraph, second sentence). One would have been motivated to use annexin binding to exposed phosphatidylserine of the cell membrane to determine how many cells receive the complex through constriction and perturbation, with a reasonable expectation of success. Given that the method is expected to constrict and perturb every cell, at least about 70% of the AACs would be expected to stain positive for annexin. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Applicant’s arguments have been addressed above.
Claims 22 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 7, 44, 64, 75, 76, 81, 85, 86, 93, 113, 123, 152, 154, 161, 181, 221, 225 and 230 of copending Application No. 17/425,709 (reference application) in view of McGann et al. (US 2006/0063141 A1, “McGann”) and Boersma et al. (J Nucl Med, 2005, 46:2035-2050, “Boersma”) as applied to claim 10 above, and further in view of Crowe et al. (US 2002/0114791 A1, “Crowe”) and Ditommaso et al. (US 2019/0017072 A1, “Ditommaso”). Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims are not directed to AAC concentrations, however, Crowe discloses a method of cryopreservation of RBCs by loading cryopreservation medium to the RBCs (see paragraph [0017], for example), wherein the cell concentration is anywhere from about 105 to 1010, 106 to 109, and 107 to 108 per ml of medium (see paragraphs [0139] and [0150]). While the particular value of 0.5x109 is not disclosed, it would have been the result of routine optimization given that the amount of cells in relation to the amount of cryopreservation medium would result in varying degrees of viable cells recovered, which is a result-effective variable. Further, the use of the term “about” to describe the amounts leaves room for the neighboring values disclosed by Crowe (outlined above). As for the post-thaw AAC concentrations, those values are a natural outcome of doing what the prior art suggests.
The copending claims are not directed to the pH of the solution. Ditomasso discloses the pH at which the complex is contacted with the cells to be between about 5.5 to about 8.5 (see paragraph [0010]). It would have been obvious to have incorporated these features into the copending claims with a reasonable expectation of success in view of the similar nature of Ditommaso’s compositions and methods. One would have been motivated to claim a pH range as these specific embodiments further define a similar core product and method recited at a higher level of generality. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Applicant’s arguments have been addressed above.
(New Provisional Rejection) Claims 1, 32 and 42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 39-41, 43, 46-49, 51, 53, 55, 58, 68, 101-103, 105 and 108-110 of copending Application No. 18/007,290 in view of McGann et al. (US 2006/0063141 A1, “McGann”) and Crowe et al. (US 2002/0114791 A1, “Crowe”). Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims are directed to a composition comprising anucleate cell-derived vesicles comprising a mutated Ras antigen, and in some embodiments, an adjuvant such as CPG (ODN), and methods of making the composition. The copending claims do not recite the embodiments of cryopreservation or cryopreservation media. However, it would have been obvious to have claimed such with a reasonable expectation of success, motivated by the convenience of preserving cells for future use, as seen in McGann (see paragraphs [0003] and [0021]). McGann discloses methods of cryopreserving cells, including RBCs, using a non-linear cooling method with DMSO in solution (see abstract, paragraphs [0003], [0009], [0014], [0015], [0111] and [0128]).
The copending claims do not disclose AAC concentrations, however, Crowe discloses a method of cryopreservation of RBCs by loading cryopreservation medium to the RBCs (see paragraph [0017], for example), wherein the cell concentration is anywhere from about 105 to 1010, 106 to 109, and 107 to 108 per ml of medium (see paragraphs [0139] and [0150]). While the particular value of 0.5x109 is not disclosed, it would have been the result of routine optimization given that the amount of cells in relation to the amount of cryopreservation medium would result in varying degrees of viable cells recovered, which is a result-effective variable. Further, the use of the term “about” to describe the amounts leaves room for the neighboring values disclosed by Crowe (outlined above). As for the post-thaw AAC concentrations, those values are a natural outcome of doing what the prior art suggests.
The copending claims are not directed to embodiments wherein the composition is sterile, however, Crowe’s pharmaceutical compositions are sterile (see paragraph [0121]). It would have been obvious to have claimed a sterile composition in order to reduce the risk of contamination, with a reasonable expectation of success. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(New Provisional Rejection) Claims 20, 30, 35 and 47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 39-41, 43, 46-49, 51, 53, 55, 58, 68, 101-103, 105 and 108-110 of copending Application No. 18/007,290 (reference application) in view of McGann et al. (US 2006/0063141 A1, “McGann”) and Crowe et al. (US 2002/0114791 A1, “Crowe”), as applied to claim 1 above, and further in view of Ditommaso et al. (US 2019/0017072 A1, “Ditommaso”). Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claims 20 and 30 are directed to embodiments wherein the pH of the formulation is about 6.0 to about 8.5, or about 7.5. Instant claim 35 is directed to an embodiment wherein the antigen is an HPV antigen. Instant claim 47 is directed to an embodiment wherein the formulation is in a vial. These embodiments are not claimed in the copending application.
Instant claim 30 is directed to an embodiment wherein the AAC concentration is about 7x109 in about 9.5 ml, which is not claimed in the pending claims. However, such a value would have been the result of routine optimization given that the amount of cells in relation to the amount of cryopreservation medium would result in varying degrees of viable cells recovered, which is a result-effective variable.
Ditommaso discloses delivery of a complex of antigen, such as HPV16 E7 synthetic long peptide, associated with an adjuvant (see paragraphs [0080], [0082]) to a cell. The method comprises constriction of cells, such as RBCs, causing perturbations that allow the complex to enter the cells (see paragraphs [0005] and [0093]). Compositions comprising pharmaceutically acceptable carriers are contemplated, as well as administration of the cells, and vials (see paragraphs [0036], [0126] and [0129]). The pH at which the complex is contacted with the cells is between about 5.5 to about 8.5 (see paragraph [0010]). It would have been obvious to have incorporated these features into the copending claims with a reasonable expectation of success in view of the similar nature of Ditommaso’s compositions and methods. One would have been motivated to claim a pH range, a particular type of antigen, and a vial, as these specific embodiments further define a similar core product and method recited at a higher level of generality. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(New Provisional Rejection) Claim 39 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 39-41, 43, 46-49, 51, 53, 55, 58, 68, 101-103, 105 and 108-110 of copending Application No. 18/007,290 (reference application) in view of McGann et al. (US 2006/0063141 A1, “McGann”) and Crowe et al. (US 2002/0114791 A1, “Crowe”) and Ditommaso et al. (US 2019/0017072 A1, “Ditommaso”), as applied to claim 35 above, and further in view of Van Der Burg et al. (US Patent 9,562,075, “Van Der Berg”) and Loughhead et al. (WO 2019/178006 A2, published 9/19/2019, “Loughhead”). Claim 39 is directed to an embodiment wherein the HPV antigens comprise SEQ ID NO: 19 and SEQ ID NO: 23. Although the claims at issue are not identical, they are not patentably distinct from each other.
Ditommaso discloses the use of any antigen, such as viral antigens (e.g., HPV16 E7 synthetic long peptide) but does not provide the sequences set forth in Applicant’s SEQ ID NO: 19 and 23. It would have been obvious to have claimed any HPV sequences with a reasonable expectation of success, such as Loughhead’s HPV16 E7 protein fragment, SEQ ID NO: 23 (see paragraph [0361]), which is identical to Applicant’s SEQ ID NO: 23, and Van Der Burg’s HPV 16 E6 protein fragment, SEQ ID NO: 12, which is identical to Applicant’s SEQ ID NO: 19 (see col. 6, line 27). One would have been motivated to use multiple sequences from HPV in view of Van Der Burg’s suggestion to use antigens from E2, E6 and E7 in order to improve immunogenicity (see col. 5, lines 46-48). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(New Provisional Rejection) Claims 10 and 16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 39-41, 43, 46-49, 51, 53, 55, 58, 68, 101-103, 105 and 108-110 of copending Application No. 18/007,290 (reference application) in view of McGann et al. (US 2006/0063141 A1, “McGann”) and Boersma et al. (J Nucl Med, 2005, 46:2035-2050, “Boersma”). Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims do not recite the embodiments of cryopreservation or cryopreservation media. However, it would have been obvious to have claimed such with a reasonable expectation of success, motivated by the convenience of preserving cells for future use, as seen in McGann (see paragraphs [0003] and [0021]). McGann discloses methods of cryopreserving cells, including RBCs, using a non-linear cooling method with DMSO in solution (see abstract, paragraphs [0003], [0009], [0014], [0015], [0111] and [0128]).
The copending claims are not directed to the percentage of cells that stain positive for annexin. However, it would have been obvious to have claimed such as a result of using annexin binding to determine the number of cells that receive the complex (i.e., successful production of AACs). Boersma discloses annexin A5 as a diagnostic tool that binds to phosphatidylserine, a marker for apoptotic cells (see abstract). In viable cells, phosphatidylserine is present on the inner side of the cell membrane (see Boersma, page 2036, left column, last full paragraph, second sentence). One would have been motivated to use annexin binding to exposed phosphatidylserine of the cell membrane to determine how many cells receive the complex through constriction and perturbation, with a reasonable expectation of success. Given that the method is expected to constrict and perturb every cell, at least about 70% of the AACs would be expected to stain positive for annexin. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Applicant’s arguments have been addressed above.
(New Provisional Rejection) Claims 22 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 39-41, 43, 46-49, 51, 53, 55, 58, 68, 101-103, 105 and 108-110 of copending Application No. 18/007,290 (reference application) in view of McGann et al. (US 2006/0063141 A1, “McGann”) and Boersma et al. (J Nucl Med, 2005, 46:2035-2050, “Boersma”) as applied to claim 10 above, and further in view of Crowe et al. (US 2002/0114791 A1, “Crowe”) and Ditommaso et al. (US 2019/0017072 A1, “Ditommaso”). Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims are not directed to AAC concentrations, however, Crowe discloses a method of cryopreservation of RBCs by loading cryopreservation medium to the RBCs (see paragraph [0017], for example), wherein the cell concentration is anywhere from about 105 to 1010, 106 to 109, and 107 to 108 per ml of medium (see paragraphs [0139] and [0150]). While the particular value of 0.5x109 is not disclosed, it would have been the result of routine optimization given that the amount of cells in relation to the amount of cryopreservation medium would result in varying degrees of viable cells recovered, which is a result-effective variable. Further, the use of the term “about” to describe the amounts leaves room for the neighboring values disclosed by Crowe (outlined above). As for the post-thaw AAC concentrations, those values are a natural outcome of doing what the prior art suggests.
The copending claims are not directed to the pH of the solution. Ditomasso discloses the pH at which the complex is contacted with the cells to be between about 5.5 to about 8.5 (see paragraph [0010]). It would have been obvious to have incorporated these features into the copending claims with a reasonable expectation of success in view of the similar nature of Ditommaso’s compositions and methods. One would have been motivated to claim a pH range as these specific embodiments further define a similar core product and method recited at a higher level of generality. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Applicant’s arguments have been addressed above.
Conclusion
Claims 61, 62 and 75 are objected to for being dependent on a rejected claim but would otherwise be allowable if rewritten in independent form.
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/STACY B CHEN/Primary Examiner, Art Unit 1672