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 .
Detailed Action
Response to Amendments
The amendments made to the claims 11/10/2025 have been entered.
Claim Objection
In view of the amendment made to the claims, the objection made in the prior office action over claim 6 is withdrawn.
Maintained Rejections
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.
KSR Rationales
The MPEP in section 2143, subsection I gives examples of Rationales for supporting a conclusion of obvious. These rationales are non-exhaustive and include (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) “Obvious to try” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Claim(s) 1- 6, 8-9, 11, 22, and 24, is/are rejected under 35 U.S.C. 103 as being unpatentable over Eagle (WO 2012/122444 A1) in view of Schinazi (EP 0471794 B1) Hurt (US 2012/0157435), Roldão (Expert Rev. Vaccines 9(10), 2010), and Papania (Platkin’s Vaccines, 2017, 1320-1353, doi: 10.1016/B978-0-323-35761-6.00068-7).
Claim 1 is drawn to a mammalian halogenated xanthene (HX) compound-adjuvanted vaccine composition that contains i) an immunogen present in a vaccine-effective amount dissolved or dispersed in a pharmaceutically acceptable diluent for parenteral administration, along with ii) an adjuvant-effective amount of a halogenated xanthene (HX) compound and one or more excipients that are present at about 0/001% by weight to about 10% by weight wherein said HX compound is rose bengal disodium.
Claim 8 is drawn to a concentrated pre-vaccine composition of the composition of claim 1 wherein the composition is present in a container and wherein the amounts of the immunogen and HX compound are predetermined to provide a vaccine-effective amount and an adjuvant effective amount of the immunogen and HX compound respectively.
Claim 11 is drawn to an improved vaccine composition that contains the vaccine-effective amount of a predetermined immunogen and about 0.0001% by weight to about 10% by weight of one or more excipients dissolved or dispersed in a pharmaceutically acceptable diluent wherein the HX compound is rose bengal disodium.
Claim 22 is to a method of enhancing a mammalian immunogen-specific immune response that comprises contacting mammalian cells present in vivo with an adjuvant-effective amount of a HX compound, wherein the HX compound is rose bengal disodium.
Dependent claim 2 is drawn to embodiment wherein the HX compound is an aromatic derivative that is an ester or amide formed from an alcohol or monosubstituted amine selected from the group consisting of the following:
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Dependent claim 3 specifies that the vaccine is an anti-microbial vaccine.
Dependent claim 4 specifies that the immunogen is a) an aliquot of peripheral blood, tumor tissue or lymphoid or lymph node tissue that contains immune anti-cancer components.
Dependent claim 9 specifies an embodiment of claim 8 wherein the immunogen and compound are dry.
Dependent claim 24 is drawn to an embodiment of claim 22 wherein the immunogen is a viral proteinaceous sequence.
Regarding claims 1- 6, 11, 22, and 24, Eagle on p. 7, para [0010] contemplates methods of treating cancer comprising administering a chemo ablative pharmaceutical composition in combination with a therapeutically effective amount of a systemic immunomodulatory anticancer agent (abstract). Eagle on p. 8-9, para. [0017]-[0020] contemplates compositions comprising rose bengal disodium. Eagle on p. 24, para. [0070] contemplates the addition of pH buffers. The instant specification on p. 16 discloses “buffer salts” as an illustrative example of an excipient.
Regarding claim 6, and 24, Eagle in para. [0013] contemplates anticancer agents including non-specific cytokines, interferons, granulocyte macrophage colony stimulating factor, dendritic cell vaccines or other allogeneic cancer vaccines including oncolytic herpes virus or plasmid encoding human leukocyte antigen, and antibodies against specific tumor antigens.
Eagle does not explicitly mention activity against microbes (viruses), derivatives of compounds, immunogens or viral proteinaceous peptide sequences, or concentrated pre-vaccine compositions. This is addressed by the combination of Schinazi, Hurt, Roldão, and Papania.
Regarding claim 3, Schinazi on p. 13, Examples 6-8 discloses the anti-viral activity of formulations comprising rose bengal against HIV infections. Anti-viral activity with and without light was calculated to have EC50 values of 1,41 and 2.38 μM respectively. This teaching indicates that the anti-virality is a property of rose bengal which would be imparted onto a composition comprising said rose bengal.
Regarding claim 2, Hurt is largely drawn to “compounds and methods for preventing and treating viral infections” (title) using compounds that contain a xanthene core (Figure 1A-E). Hurt on p. 6, para. [0049] teaches heteroaryl groups (aromatic rings that contain 1-4 heteroatoms) that may act as substituents (derivatives). Note that rose bengal is stated to be a halogenated xanthene by the instant disclosure. Therefore, one of ordinary skill in the art would have found it obvious to be able to modify the rose bengal compound to create derivatives.
Regarding claims 4 and 24, Roldão on p. 1149, left col., states “To avoid widespread dissemination of FMDV, scientists discovered in the 1970s that a vaccine could be produced by using only a single key protein from the virus. Almost a decade later, Kleid and colleagues succeeded in cloning the antigenic polypeptide VP3 of FMDV within Escherichia coli and preparing it as a vaccine used for cattle and swine.” This teaching indicates that it is common practice to incorporate a critical protein peptide sequence into a vaccine. Therefore, one of ordinary skill in the art would fine claims 4 and 24 obvious over this teaching.
Regarding claims 8 and 9, Papania on p. 1320, sec. Presentation states “Most vaccines are formulated, packaged, and shipped as liquids in single- or multidose vials or prefilled syringes. All others are first formulated as liquids, packaged in vials, and then lyophilized to enhance their stability. Although they are shipped in a dry format, lyophilized vaccines must be accompanied by a liquid diluent and reconstituted before on-site filling of the administration device and vaccination.” Therefore, one of ordinary skill in the art would have found a concentrated pre-vaccine formulation obvious.
Eagle teaches formulations comprising rose bengal and an immunogen with possible excipients for administration as a vaccine. Eagle contemplates administration to treat tumors. Schinazi teaches rose bengal is effective as an antiviral. Roldão teaches that it is common within the art to create vaccines comprising viral protein sequences in order to elicit an immune response. Papania teaches vaccine reconstitution requires a concentrated pre-vaccine formulation that is dried via lyophilization.
Therefore, it would have been prima facie obvious at the time of the effective filing date for one of ordinary skill in the art to have combined the teachings above to reach the instant claims with a reasonable assumption of success. One of ordinary skill would find motivation to make the combinations for the following reasons. Eagle teaches anti-cancer vaccines comprising rose bengal disodium and an immunogen. Schinazi’s teachings would allow on of ordinary skill in the art to repurpose the formulations of Eagle to treat viral infections instead. Roldão makes obvious the use of viral protein sequences in vaccines in order to elicit a stronger immune response. Papania teaches that vaccine formulations can be concentrated via lyophilization in order to ship and/or keep stable a vaccine for later use.
Claim(s) 1- 6, 8-9, 11, 22, and 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Eagle (WO 2012/122444 A1) in view of Singer (US 10,130,658, published 2018), Hurt (US 2012/0157435), Roldão (Expert Rev. Vaccines 9(10), 2010), and Papania (Platkin’s Vaccines, 2017, 1320-1353, doi: 10.1016/B978-0-323-35761-6.00068-7).
Discussion of Eagle, Hurt, Roldão, and Papania from the 103 rejection above is incorporated here.
Singer is drawn to methods of creating a composition comprising a “induced immune anticancer agents” that are isolated after intralesional administration of a halogenated xanthene (title). Regarding claims 1-12 and 22-24, and specifically claim 11, Singer in col. 3, l. 54- col. 4, l. 13 teaches that halogenated xanthenes, such as PV-10, can elicit tumor-specific immune responses (HMGB1). This immune response releases tissue that can be excised and then reintroduced (as an immunogen as in the instant claims) to treat or inhibit further cancers. Additionally, Singer on col. 5, l. 45 states “An advantage of the invention is it provides an augmented immunologically-based treatment.”
Considering the above, one of ordinary skill in the art would find it obvious to combine the methods of Singer with the compositions and methods of Eagle, along with the teachings of Schinazi, Hurt, Roldão, and Papania in order to arrive at the instant claims.
Therefore, it would have been prima facie obvious at the time of filing for one of ordinary skill in the art to have combined the teachings above in order to arrive at the instant claims with a reasonable assumption of success. One of ordinary skill in the art would have found motivation to make the combination as Singer teaches that inclusion of said immunogen lead to augmented therapy.
Response to Arguments
Applicant argues that “independent claim 1 and 11 are generally directed to a halogenated compound-adjuvanted vaccine composition including an adjuvant-effective amount of a halogenated xanthene (HX) wherein said HX is rode bengal disodium”. Applicant continues and states “Independent claim 22 is directed to a method of enhancing immunogen-specific immune response comprising contact mammalian cells with an adjuvant-effective amount of a halogenated xanthene (HX) wherein said HX is rose bengal disodium.”
Applicant states that “…one skilled in the art reading Eagle beyond the abstract would not arrive at the claimed invention as the disclosure in Eagle is very different than the claimed invention. As a result, the Office’s use of Eagle in the rejection is improper and incorrect, and the Office’s attempted combination of Eagle with the other cited references is improper.” Applicant then argues “Eagle is directed to an intralesional administered halogenated xanthene. The halogenated xanthene of the claimed invention of the present application is not administered intralesionally” (emphasis added by applicant). The present application clearly distinguishes between intralesional and the claimed adjuvant vaccine composition.” Applicant points to para. [0004] and [0041] of Eagle to emphasize that the composition of Eagle is administered intralesionally into a tumor and is not a vaccine.
Applicant then cites the instant specification p. 20-21 and recites the following paragraph:
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Applicant follows stating “Hence, the inventors of the present application are teaching that something different occurs when an HX compound is used as adjuvant compared to that which occurs when a same compound is injected intralesionally into a cancerous tumor as is disclosed in the recited patents and Eagle.”
Finally, applicant, in regards to the term “adjuvant-effective amount”, argues that “That portion of the specification [full paragraph on p. 34] defines an ‘adjuvant amount’ as ‘that amount that induces a Type I IFN immune reaction. Such an amount is also an amount of HX compound that is less than cytotoxic amount and preferably less than about 75% of a cytotoxic amount” (emphasis added by applicant).” Applicant then calculates that “a typical adjuvant-effective amount of a HX compound in a mammalian HX-compound-adjuvanted vaccine composition based on RB as the HX compound is about 35 to about 75 mg/L or about 7.5 x 10-5 to about 7.5 x 10-6 molar.”
As stated above, claims 1, 8, and 11 are drawn to compositions comprising the rose bengal disodium. While Eagle’s claims are drawn to methods, the methods involve the administration of a composition comprising a halogenated xanthene. Critically, Eagle in para. [0076] states “Typical doses of the IL chemoablative pharmaceutical composition administered by IL administration range from between 0.1 mL/cc lesion volume to about 2 mL/cc lesion volume…Such doses typically correspond to a patient dose of between 10 mg to about 1500 mg of halogenated xanthene.” This range encompasses the amounts discussed by application in regards to “cytotoxic amount”.
Essentially, the claimed compositions are a combination of rose bengal disodium and an immunogen in amounts that are taught by the art. The route of administration and the specific amounts do not change the structure of the composition sufficiently from what is taught within the art.
Regarding the second 103 rejection further including Singer, applicant states:
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The argument is a repetition of the arguments against the first 103 rejection.
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.
Patent 11,975,106
Claims 1- 6, 8-9, 11, 22, and 24 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 11,975,106 in view of Eagle, Schinazi, Hurt, Roldão, and Papania (cited above).
The reference claims are drawn to a method of treating Sars-CoV-2 virus infection comprised of administering a halogenated fluorescein compound (rose bengal or rose bengal disodium). Considering that the methods comprise administering a composition comprising rose bengal, the instant claims would be obvious over the reference claims.
Patent 11,071,781
Claims 1- 6, 8-9, 11, 22, and 24 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-33 of U.S. Patent No. 11,071,781 in view of Eagle, Schinazi, Hurt, Roldão, and Papania (cited above).
Reference claim 1 is shown below.
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Similarly, the other reference claims are drawn to methods that comprise administering a composition comprising rose bengal and additional immunomodulatory anticancer agents.
Patent 10,471,144
Claims 1- 6, 8-9, 11, 22, and 24 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 10,471,144 in view of Eagle, Schinazi, Hurt, Roldão, and Papania (cited above).
Reference claim 1 is shown below.
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Reference claims 11 and 12 are drawn to similar methods comprising administration of a chemo ablative pharmaceutical composition and a systemic immunomodulatory anticancer agent. Dependent claims 2 and 13 state the composition comprises rose bengal. Reference claim 11 states the composition comprises rose bengal.
Patent 9,839,688
Claims 1- 6, 8-9, 11, 22, and 24 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 9,839,688 in view of Eagle, Schinazi, Hurt, Roldão, and Papania (cited above).
Similar to the non-statutory double patenting rejections above, the reference claims are drawn to a pharmaceutical composition comprising an “intralesional chemo ablative pharmaceutical agent” and a “systemic immunomodulatory anticancer agent.”
Patent 9,808,524
Claims 1- 6, 8-9, 11, 22, and 24 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 9,808,524 in view of Eagle, Schinazi, Hurt, Roldão, and Papania (cited above).
Similar to the non-statutory double patenting rejections above, the reference claims are drawn to a method of treatment of a melanoma comprising administering a pharmaceutical composition comprising an “intralesional chemo ablative pharmaceutical agent” and a “systemic immunomodulatory anticancer agent.”
Response to Arguments
Applicant argues that “double patenting is directed to the claims. The claims of the present application are directed to an adjuvant vaccine. None of the claims of these cited patents recites nor is directed to an adjuvant vaccine. As explained above, this is a patentably distinct feature not recited in the claims of these cited patents.”
The reference claims are all drawn either to a method comprising administering a halogenated xanthene or a composition comprising a halogenated xanthene. For similar reasons discussed in the 103 rejections above, the combination of the reference patents and the cited references make the instant composition, comprising an immunogen in a vaccine effective amount and rose bengal disodium in adjuvant-effective amount, obvious.
Conclusion
No claims allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LUISALBERTO GONZALEZ whose telephone number is (571)272-1154. The examiner can normally be reached M-F 8:30-5:30.
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/L.G./Examiner, Art Unit 1624
/SUSANNA MOORE/Primary Examiner, Art Unit 1624