DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 3/19/2025 has been considered by the examiner.
Specification
The use of the term “Qdenga”, which is a trade name or a mark used in commerce, has been noted in paragraph [0078] of the instant published application, USPgPub 2024/0216498. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Applicant is required to properly annotate all trade names and/or marks present in the instant specification, if any additional trade names and/or marks are discovered.
The incorporation of essential material in the specification by reference to an unpublished U.S. application, foreign application or patent, or to a publication is improper. Paragraph [0150] of the instant published disclosure, USPgPub 2024/0216498, states: “Xiao et al., Exp. Neurobiol. 144:113-124, 1997, or Fisher et al., J. Virol. 70:520-532, 1996, the disclosures of both of which are incorporated herein by reference.” Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(g).
Applicant' s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claims 45 and 49 are objected to because of the following informalities: “wherein large- scale comprises production cultures of surface area 35,000 cm2 or more”, is ungrammatical.
Claims 47 and 51 are objected to because of the following informalities: “TDV-” presumably stands for “tetravalent dengue virus” according to paragraph [0078] of the instant published application, USPgPub 2024/016498. Acronyms should be spelled out prior to first use.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2-4 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Instant claim 2 recites, “the harvest does not undergo a freezing step until the step of processing the bulk drug substance.”
Instant claim 3 recites, “wherein processing the bulk drug substance does not involve a freezing step before the filtration step”.
Instant claim 4 recites, “wherein the harvest does not undergo a freezing step until the step of processing the bulk drug substance and wherein processing the bulk drug substance does not involve a freezing step before the filtration step.”
Instant claim 1 requires harvesting a bulk drug substance, filtering the bulk drug substance, followed by freezing the bulk drug substance. Therefore, claims 2-4 fail to further limit claim 1.
Claims 19-21 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Instant claim 19 recites, “the at least two harvests do not undergo a freezing step until the step of processing the at least two bulk drug substances.”
Instant claim 20 recites, “wherein processing the at least two bulk drug substances does not involve a freezing step before the filtration step.”
Instant claim 21 recites, “wherein each of the at least two harvests do not undergo a freezing step until the step of processing the at least two bulk drug substances and wherein processing the at least two bulk drug substances does not involve a freezing step before the filtration step.”
Claim 17, from which claims 19 and 21 depend, already requires obtaining at least two harvests, filtering each of the at least two bulk drug substances followed by a step of freezing each of the at least two bulk drug substances to obtain at least two frozen bulk drug substances.
Therefore, claims 19-21 fail to further limit claim 17.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 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.
Claims 6, 8, 11, 12, 15, 16, 26-29, 32, 33, 44, 46, 48, and 50 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.
Regarding claims 6, 11, 12, 28, 29, 46, and 50, the phrase “such as” renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claims 15, 16, 32, and 33 refer to “high” or “higher” viral titers, which are relative terms, rendering the claims indefinite. Viral titers are not defined by the claim and the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Without a quantity for comparison, the requisite “high” or “higher” viral titers required are indeterminable.
Lines 6-7 of claim 26 states, “a composition comprising a buffer flush and drug substance, which is the bulk drug substance”. Since the bulk drug substance is defined as comprising buffer flush and drug substance, it is not clear what the difference between the materials comprised by: “at least two drug substances and at least two bulk drug substances” recited in line 8. This same confusion exists in claim 27. There is also no apparent difference between the materials obtained in claims 28 and 29: “at least two processed harvests, at least two purified harvests, at least two drug substances and at least two bulk drug substances”.
Regarding claims 44 and 48, it is unclear whether the limitation, “tetravalent dengue vaccine TAK-003”, following the phrase is part of the claimed invention. See MPEP § 2173.05(d).
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 1-6, 9-21, and 26-33 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (USPgPub 2019/0270970) and Wolf et al. (Expert Review of Vaccines. 2011; 10 (10): 1451-1475).
Liu et al. teach a method of large-scale Vero cell production in paragraphs [0230 and 0392-0394] of an attenuated flavivirus vaccine, including dengue or Japanese encephalitis viruses, in paragraphs [0016, 0203, 0204, 0205, 0335, 0498] and claim 42. In paragraphs [0229-0233], the method of Liu et al. requires a Vero cell culture that is infected with a virus at a multiplicity of infection (MOI) of less than 0.01 prior to harvesting, i.e., removal of supernatant, to obtain a harvest comprising a bulk drug substance (defined as flavivirus vaccine components in paragraph [0396], for example, of the instant published USPgPub 2024/0216498), as required in instant claims 1, 13, 14, 30, and 31. The method of Liu et al. requires processing each harvest by application to a hydroxyapatite column and a stabilizing phosphate buffer in to clarify and stabilize the harvest, followed by anion exchange chromatography, followed by ultrafiltration in paragraphs [0011, 0014, 0017, 0018, 0054-0064, 0167-0183, 0201, 0332], and claim 39, as required by instant claims 9-12 and 26-29. Paragraph [0233] of Liu et al. teach at least 2 or at least 8 successive harvests from the same bioreactor, as required by instant claim 17. Paragraphs [0121, 0187, 0201, and 0266, for example] discuss observing virus titer and virus potency per dose, corresponding to the relatively “high virus titres” required in instant claims 15, 16, 32, and 33. Further vaccine processing includes freezing each bulk vaccine in paragraphs [0237-0245, 0273 and 0499-0501], as required in instant claims 1-4, 17, and 19-21. Paragraphs [0505-0515] of Liu et al. describe thawing the lyophilized vaccine product to determine heat stability, as required by instant claim 18.
Though Liu et al. do not mention agitating the bulk flavivirus vaccine for at least one minute during filtering, as recited in instant claims 5 and 6, it would have been prima facie obvious to one of ordinary skill in the art prior to the invention was made to have agitated the bulk flavivirus vaccine during filtering to optimize viral precipitation and membrane retention.
While the ultrafiltration step of Liu et al. necessitates the presence of at least one washing/ flushing buffer, as recited in instant claims 9-12 and 26-29.
In “Ultrafiltration” on page 1458, Wolf et al. teach it is an efficient, high-throughput technique.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have used at least one washing/ flushing buffer in the ultrafiltration step of Liu et al. to concentrate viruses, as taught by Wolf et al. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have used at least one washing/ flushing buffer in the ultrafiltration step of Liu et al. because Wolf et al. teach ultrafiltration is the preferred method of virus concentration and buffer exchanges in vaccine manufacturing processes and is applicable to large-volume processing.
Claims 7, 44, 46, 48, and 50 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. and Wolf et al. as applied to claims 1-6, 9-21, and 26-33 above, and further in view of Gallina et al. (WO 2017/041156).
See the teachings of Liu et al. and Wolf et al. above. While Liu et al. teach freezing each bulk vaccine in paragraphs [0237-0245, 0273 and 0499-0501], Liu et al. do not teach the temperature the freezing takes place, recited in instant claim 7. Liu et al. also teach the method of large-scale Vero cell production of dengue or Japanese encephalitis viruses, in paragraphs [0016, 0203, 0204, 0205, 0335, 0498] and claim 42, but does not mention that the vaccine is divalent, trivalent, or tetravalent, recited in instant claims 44 and 48, or that the live, attenuated dengue virus is selected from serotypes 1-4, recited in instant claims 46 and 50.
Gallina et al. teach an attenuated tetravalent dengue vaccine comprising serotypes 1-4, see claim 1 and storing the filtered dengue at -80° C in claim 5.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have combined four dengue serotypes into one tetravalent vaccine formulation, as taught by Gallina et al., to prevent dengue infection, see paragraphs [0005 and 0006]. One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have purified the dengue tetravalent vaccine of Gallina et al. by the method of Liu et al. and Wolf et al. to produce a highly intact, homogenous, and stable enveloped vaccine composition for clinical use, see the abstract and paragraph [0046] of Liu et al. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have purified the dengue tetravalent vaccine by the method of Liu et al. and Wolf et al. with the tetravalent dengue vaccine of Gallina et al. because both Liu et al. and Gallina et al. manufacture attenuated dengue virus vaccines through successive harvests of large-scale Vero cell production, see paragraphs [0016, 0203, 0204, 0205, 0230, 0233, 0335, 0392-0394, 0498] and claim 42 of Liu et al. and paragraphs [0011-0013] and claims 1-3, 5, and 11 of Gallina et al.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have frozen the attenuated tetravalent dengue vaccine of Gallina et al. prepared by the method of Liu et al. and Wolf et al. at -80° C to maintain stability during storage, absent evidence to the contrary.
Claims 8, 45, and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. and Wolf et al. as applied to claims 1-6, 9-21, and 26-33 above, and further in view of Berrie et al. (Vaccine. 2020 Apr 29; 38 (20): 3639-3645).
See the teachings of Liu et al. and Wolf et al. above. Liu et al. teach a large-volume bioreactor comprising 500-2000L in paragraph [0230]. However, Liu et al. do not teach the weight of the frozen bulk attenuated vaccine to be at least 100 g, recited in instant claim 8 or the surface area for the cultures of at least 35,000 cm2, recited in instant claims 45 and 49.
Berrie et al. teach a 10 m2 bioreactor in section 2.1.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have manufactured the attenuated flavivirus vaccine of Liu et al. and Wolf et al. in the 10 m2 bioreactor of Berrie et al. to achieve higher production of virus per surface
area and increase number of doses per harvest after combining, taught by Liu et al. to acquire 100 grams, see Table 2 of Berrie et al. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have manufactured the attenuated flavivirus vaccine of Liu et al. and Wolf et al. in the 10 m2 bioreactor of Berrie et al. because both Liu et al. and Berrie et al. propagate virus in Vero cells and repeat multiple harvests, see section 2.2 and Table 2 of Berrie and paragraphs [0229-0233] of Liu et al.
Claims 47 and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. and Wolf et al. as applied to claims 1-6, 9-21, and 26-33 above, and further in view of SEQ 1 alignment with Geneseq db access no BBG25551 in US2014134205 by Livengood et al. 2014.
See the teachings of Liu et al. and Wolf et al. above. Neither reference teaches SEQ ID NO: 1, as required.
The sequence alignment of Geneseq db access no BBG25551 shares 100% identity with instant SEQ ID NO: 1.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have propagated the Geneseq db access no BBG25551 in the method of Liu et al. and Wolf et al. because the description provided with the alignment teaches that the sequence is effective for inducing an immune response against dengue and is part of a live, attenuated chimera. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have propagated the Geneseq db access no BBG25551 in the method of Liu et al. and Wolf et al. because Liu et al. teach the large-scale propagation method is applicable to dengue viruses in paragraphs [0016, 0203, 0204, 0205, 0335, 0498] and claim 42.
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, 9-17, 50, and 51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 99, 101, 102, 109, 110, 114-118, 131, and 132 of copending Application No. 18/832,973 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 99, 101, 102, 109, 110, 114-118, 131, and 132 of ‘973 anticipate a method for large-scale flaviviral vaccine production and manufacture comprising the following sequential steps: providing cells in growth media, infecting the cells with an attenuated dengue selected from serotypes 1-4 comprising any one of SEQ ID NOs: 1-8 at a low multiplicity of infection less than 0.008 (MOI), harvesting to obtain a harvest, clarifying and stabilizing the harvest to obtain a processed harvest, and purifying the processed comprising at least one anion exchange chromatography step and at least one flushing step in ultracentrifugation and freezing the bulk dengue virus vaccine, anticipating claims 1, 9-14, 17, 50, and 51. The method steps of ‘973 anticipate obtaining the high viral titers of instant claims 15 and 16.
Claims 1, 9-13, 15-17, 50, and 51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 103-105, 108, 110, 117, 121, and 126-129 of copending Application No. 18/832,969 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 103-105, 108, 110, 117, 121, and 126-129 of ‘969 anticipate a method for large-scale flaviviral vaccine production and manufacture comprising attenuated dengue selected from serotypes 1-4 comprising any one of SEQ ID NOs: 1-8, harvesting to obtain a harvest, clarifying and stabilizing the harvest with a buffer to obtain a processed harvest, and purifying the processed comprising at least one anion exchange chromatography step and at least one flushing step in ultracentrifugation and freezing the bulk dengue virus vaccine, anticipating claims 1, 9-14, 17, 50, and 51. The method steps of ‘973 anticipate obtaining the high viral titers of instant claims 15 and 16.
Claims 1-21, 26-33, and 44-51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-35 and 39-47 of copending Application No. 19/133,382 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the method steps of large-scale flavivirus vaccine production and conditions and materials required for each step of ‘382 anticipate instant claims 1-21, 26-33, and 44-51.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHANON A FOLEY whose telephone number is (571)272-0898. The examiner can normally be reached M-F, generally 5:30 AM-5 PM, flexible.
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/Shanon A. Foley/Primary Examiner, Art Unit 1671
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