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 6/11/2024 and 4/1/2026 have been considered by the examiner.
Specification
The incorporation of essential material in the specification by reference to an unpublished U.S. application, foreign application or patent, or to a publication is improper.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 [0001] of the instant published disclosure, USPgPub 2024/0316177, incorporates PCT International Application No. PCT/US2019/024836 and U.S. Provisional Application No. 62/650,406, and paragraph [0059] incorporates PCT/US2008/073479; PCT/US2011/034484; and PCT/US2012/062998. Paragraph [0099] states: “All publications, patent applications, patents, patent publications, and other references cited herein are incorporated by reference in their entireties for the teachings relevant to the sentence and/or paragraph in which the reference is presented.” 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).
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
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.
Claim 8 is 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. Claim 8 requires a peptide of SEQ ID NOs: 1-3, already recited in claim 2, from which claim 8 depends. 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 16 is 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. Claim 16 is drawn to a composition comprising a poliovirus immunogen, already recited in line 1 of claim 1. 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 1-20 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.
Instant claims 1 and 16 are drawn to an “inactivated poliovirus”… “comprising an attenuated and/or neuropathogenic strain of poliovirus serotype 1, 2 and/or 3”. Claims 4 and 5 require that the inactivated poliovirus comprises one or more attenuated Sabin or S19 strains, respectively, and claims 17 and 18 require two or more an attenuated and/or neuropathogenic strains of poliovirus serotype 1, 2 and/or 3. It is unclear how an inactivated poliovirus comprises an attenuated and/or neuropathogenic strain of poliovirus since the first poliovirus recited is required to be inactivated/ killed. It cannot be determined whether the inactivated poliovirus immunogen is intended to be recited as a product-by-process, gleaned from claim 2, paragraph [0010], and Examples 1-4, beginning on page 10 of the instant published disclosure, USPgPub 2024/0136177, or as a distinct product, i.e., an inactivated poliovirus.
Claim 6 recites the limitation "the divalent cation" in line 1. There is insufficient antecedent basis for this limitation in the claim. There is no recitation of a cation in claim 1, from which claim 6 depends. The scope of the claim is indeterminate. In the interest of compact prosecution, claim 6 is treated as if it depends from claim 2. However, this courtesy does not preempt the requirement for a clarifying amendment.
Claim 9 recites the limitation "at least a portion of the epitopes" in lines 2-3. While epitopes are an inherent component of a poliovirus, it cannot be determined whether the epitopes of claim 9 are referring to the inactivated, attenuated, and/or neuropathogenic poliovirus of claim 1. There is insufficient antecedent basis for this limitation in the claim. Further ambiguity arises from whether the “at least a portion” is pointing to: undamaged or active, recited in line 2. Additionally, “undamaged” or “active” epitopes allude to unrecited structural distinctions that are not discussed in the instant disclosure. It is not clear what is intended by these limitations.
Claims 10-13 state that the poliovirus immunogen made by the method stimulates neutralizing antibodies. It is not clear how any immune response is induced without an administration step. This rejection affects all dependent claims.
Claim 14 recites the limitation "the method" in line 1. There is insufficient antecedent basis for this limitation in the claim. The lack of active steps recited in claim 1, from which claim 14 depends, renders the scope of the claim indeterminate.
Claim15 recites the limitation "the D antigen content" in line 1. While a D antigen content is an inherent component of a poliovirus, it cannot be determined whether the D antigen of claim 15 is referring to the inactivated, attenuated, and/or neuropathogenic poliovirus of claim 1. There is insufficient antecedent basis for this limitation in the claim.
Regarding claim 19, the parenthesized phrase "(e.g., QS-21)”, renders the claim indefinite because it is unclear whether the phrase is part of the claimed invention or not. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 9 is 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 written description rejection.
Claim 9 recites the limitation "at least a portion of the epitopes" in lines 2-3. While epitopes are an inherent component of a poliovirus, it cannot be determined whether the epitopes of claim 9 are referring to the inactivated, attenuated, and/or neuropathogenic poliovirus of claim 1, from which claim 9 depends. The "at least a portion of the epitopes" recited in claim 9 are required to be “undamaged and/or active”, recited in line 2. These two characteristics allude to unrecited structural epitope distinctions that are not discussed in the instant disclosure. An undamaged epitope may encompass an undenatured structure that is specific to a monoclonal antibody (Mab) and an active epitope may encompass a denatured structure that retains functional affinity to a Mab. See “Conditional Epitopes” in Willingham. “Conditional epitopes: is your antibody always specific?”. Journal of Histochemistry & Cytochemistry. 1999 Oct; 47 (10): 1233-1235).
As taught in Greenspan et al (Nature Biotechnology 17:936-937 (1999)) defining epitopes is not as easy as it seems (page 937). Epitopes have been defined in terms of the spacial organization of residues that make contact with a ligand and the structural characterization of the molecular interface for the binding of the molecules to define the epitope boundaries (page 937 middle of page). The epitope defined in this manner will likely include residues that contact the ligand but are energetically neutral or even destabilizing to binding. “In addition, a priori it will not include any residue that makes no contact with a ligand but whose substitution may profoundly affect ligand recognition through influence on the stability of the free form of the macromolecule, or participation in long-range allosteric effects”. “Even when the residues making contacts with ligands are known with certainty, say from the crystal structure of the complex, the question remains with regard to the energetic involvement of each residue (page 936 right column, first paragraph). Therefore, “amino acids should be recognized to have multiple ways of contributing to a noncovalent interaction” (page 937, middle of page). As evidenced by Greenspan et al a number of factors not primarily related to the contours of the contacts of the molecules contribute to the free energy change, sometimes profoundly.
The applicable standard for the written description requirement can be found in MPEP 2163; University of California V. Eli Lilly, 43 USPQ2d 1398 at 1407; PTO Written Description Guidelines; Enzo Biochem Inc. V. Gen-Probe Inc., 63 USPQ2d 1609; Vas- Cath Inc. V. Mahurkar, 19 USPQ2d 1111; and University of Rochester V. G.D. Searle & Co., 69 USPQ2d 1886 (CAFC 2004). To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In the instant case, no epitope is disclosed. The skilled artisan would not predict or recognize the requisite structures encompassed by the instant “undamaged and/or active” epitopes, as evidenced by Willingham et al. and Greenspan et al., respectively.
Vas-Cath Inc. V. Mahurkar, 19USPQ2d 1111, clearly states "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116). Conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers V. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
There is no disclosure of sufficient characteristics of the epitopes claimed to allow persons of ordinary skill in the art to recognize that applicants were in possession of the exponential quantity of epitopes encompassed by claim. The specification does not provide adequate written description of the epitopes attributed as “undamaged and/or active”. The specification does not clearly allow persons of ordinary skill in the art to recognize that the inventors invented what is claimed. The claims do not meet the written description provision of 35 U.S.C. 112, first paragraph.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 4, and 16-20 are rejected under 35 U.S.C. 102(a)(1/(a)(2) as anticipated by Contorni et al. (USPgPub 2015/0224185).
Instant claims 1 and 16 are drawn to a composition comprising an inactivated poliovirus, interpreted under plain meaning as per MPEP 2111.01.
Contorni e al. anticipate a composition comprising an inactivated poliovirus of serotypes, 1, 2, and 3, see claims 1, 2, 9, 13, and 20, anticipating instant claims 1 and 16-18, including one or more Sabin strains in paragraph [0090], anticipating instant claim 4. Claim 36 of Contorni et al. anticipates the composition as a vaccine, required by instant claim 20. Paragraphs [0057, 0087, and 0127] of Contorni et al. anticipate the adjuvant as an aluminum hydroxide, as recited in instant claim 19.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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 2, 3, and 6-15 are rejected under 35 U.S.C. 102(a)(1/(a)(2) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Contorni et al. (USPgPub 2015/0224185). *Note: Instant claim 6 is treated as depending from claim 2, as discussed above.
Incorporated herein: Contorni et al. anticipate a composition comprising an inactivated poliovirus of serotypes, 1, 2, and 3, see claims 1, 2, 9, 13, and 20, including one or more Sabin strains in paragraph [0090]. Claim 36 of Contorni et al. anticipates the composition as a vaccine. Paragraphs [0057, 0087, and 0127] of Contorni et al. anticipate the adjuvant as an aluminum hydroxide.
Claims 2, 3, 6, 7, and 8, described in product-by process terms, reasonably appear to encompass the claimed inactivated poliovirus, which are indistinguishable from the reference inactivated polioviruses produced by a different process. Since the patent office does not have facilities to perform comparisons between claimed materials and prior art materials, a lesser burden of proof is required to make a prima facie case of obviousness for products claimed in terms of the process used to make them. The production of the inactivated poliovirus by a particular process, i.e., exposing the poliovirus to Mn2+, one or more of SEQ ID NOs: 1-3, and a phosphate buffer in the presence of UV, does not impart novelty or unobviousness to an inactivated poliovirus when the same inactivated poliovirus is taught by the prior art.
When the reference teaches a product that appears to be the same as, or an obvious variant of, the product set forth in a product-by-process claim although produced by a different process. See In re Marosi, 710 F.2d 799, 218 USPQ 289 (Fed. Cir. 1983) and In re Thorpe, 777 F.2d 695, 227 USPQ 964(Fed. Cir. 1985). See also MPEP § 2113. Therefore, even if a particular process used to prepare a poliovirus is novel and unobvious over the prior art, the poliovirus per se, even when limited to the particular process, is unpatentable over the same poliovirus taught by the prior art. For these reasons, the instant invention as claimed is seen as prima facie obvious, if not anticipated by the Contorni et al.
Instant claims 9-12 recite epitopes of the inactivated poliovirus and/or stimulation of neutralizing antibodies. Claims 13-15 are drawn to D antigen content of the inactivated poliovirus. However, where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially
identical processes, a prima facie case of either anticipation or obviousness has been established according to In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977), “Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.). There, the inactivated poliovirus Contorni et al. is reasonably equivalent or substantially equivalent under In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977).
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 1-10, 13, 14, 16-18, and 20 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 6-14 of U.S. Patent No. 12,042,533. Although the claims at issue are not identical, they are not patentably distinct from each other because instant claim 1 can reasonably interpreted as a product-by-process, gleaned from claim 2 dependency, discussed under 35 USC 112(b) above.
Instant claims 1 and 2 are drawn to an inactivated poliovirus immunogen, by exposing an attenuated strain of poliovirus serotype 1, 2, and/or 3 poliovirus to a divalent cation which is Mn.2+, a peptide which comprises any one or any of SEQ ID NO:1-3, and a phosphate buffer; and then exposing the poliovirus in the presence of the divalent cation, peptide, and buffer to ultraviolet radiation in an amount sufficient to inactivate the poliovirus, thereby providing the inactivated poliovirus immunogen, wherein the poliovirus immunogen stimulates neutralizing antibodies as determined in the standard Wistar rat model when administered to a subject.
Claims 1 and 2 of ‘533 are drawn to a method of producing an inactivated poliovirus immunogen, by exposing an attenuated strain of poliovirus serotype 1, 2, and/or 3 poliovirus to a divalent cation which is Mn.2+, a peptide which comprises any one or any of SEQ ID NO:1-3, and a phosphate buffer; and then exposing the poliovirus in the presence of the divalent cation, peptide, and buffer to ultraviolet radiation in an amount sufficient to inactivate the poliovirus, thereby providing the inactivated poliovirus immunogen, wherein the poliovirus immunogen stimulates neutralizing antibodies as determined in the standard Wistar rat model when administered to a subject.
Therefore, the instant product claimed has no structural or functional difference from the products produced by the process recited in claims 1 and 2 of ‘533. MPEP § 806.05(f) states:
A process of making and a product made by the process can be shown to be distinct inventions if either or both of the following can be shown: (A) that the process as claimed is not an obvious process of making the product and the process as claimed can be used to make another materially different product; or (B) that the product as claimed can be made by another materially different process
In the instant case, neither (A) or (B) can be satisfied to show patentable distinctness because the patented process of ‘533 as claimed, is an obvious process of making the instant product-by-process and the process of ‘533 as claimed cannot be used to make another materially different product in view of identical materials and method steps iterated in the method of ‘533 and the instant product-by-process. The instant product-by-process, as claimed, cannot be made by another materially different process other than the ‘533 process claimed.
Claims 3 and 6-14 of ‘533 correspond to the limitations recited in instant claims 9, 7, 8, 4, 5, 10, 13, and 14, respectively.
For these reasons, the instant product-by-process claims are not patentably distinct from the method claims of ‘533.
Conclusion
Instant Figure 2C depicts clear physical distinctions between non-irradiated (top) and gamma-irradiated poliovirus particles in the presence (bottom) or absence of (middle) manganous-decapeptide-phosphate (MDP) by electron microscopy. Figures 6-9 depict neutralization titers (nAb) from subjects immunized with UVC-inactivated poliovirus in the presence or absence of (MDP) complex, where the presence of MDP maintains intact conformation of the D antigen. Claims reciting complete composition components and structural distinctions imparted by MDP on the claimed irradiation-inactivated poliovirus from the data presented are encouraged. For example:
“A manganous-decapeptide comprising SEQ ID NO: 1-phosphate (MDP) complexed with an irradiated-inactivated poliovirus.” (Support from paragraphs [0012, 0060, 0067, 0071, and 0084].) Or, “An irradiation-inactivated poliovirus comprising an intact D-antigen substantially equivalent to un-irradiated poliovirus.” (Support from paragraph [0015], Figure 2C, and Example 1.) These examples are merely suggestions in hopes of helpful assistance to applicant.
Gayen et al. (Vaccine. 2017; 3672-3681) teach epitope preservation of inactivated alphaviruses, Chikungunya virus (CHIKV) and Venezuelan equine encephalitis virus (VEEV), in the presence of a synthetic Mn-decapeptide-phosphate complex (MnDpPi, aka, “MDP”) upon gamma-irradiation. See the abstract, sections 2.1, 2.3, and Figures 1 and 2. Figure 3 of Gayen et al. shows degradation of viral genomic RNA. In the paragraph bridging pages 3639-3640, Gayen et al. state (emphasis underlined for convenience):
…Typically, as the genome size of an organism decreases, a larger dose of IR is required to inactivate a pathogen. Although the simplicity and absence of additional purification steps makes IR-based vaccine development a potentially efficient and cost effective approach, IR-induced oxidative damage to epitopes at high doses of IR (>30 kGy) typically needed
to inactivate the genomes of many viruses renders such vaccine preparations only poorly protective due to epitope damage [32,33]. Strategies that reduce IR doses in order to prevent protein oxidation are invariably accompanied by an increasing risk of incomplete inactivation of viral genomes. Such incomplete inactivation of whole-virus vaccines has led to several outbreaks [5–7].
Tobin et al. (PloS One. 2020 Jan 30; 15 (1): e0228006, post-filing publication by the inventors and others) teach total inactivation of poliovirus and protection of surface proteins during supra-lethal irradiation (45kGaγ) when combined with MDP, see “Virus irradiation” and Figures 1 and 3. In the first full paragraph on page 14, Tobin et al. state (emphasis underlined for convenience):
Generally, the probability that sparsely ionizing radiation will result in lethal damage is directly correlated to the size of the genome. As a rule, far higher doses of radiation (e.g., 20–45 kGy) are required to inactivate viruses as compared to bacteria or mammalian cells because of disparities in genome sizes.
Therefore, while Gayen et al. opine that the addition of MnDpPi (MDP) prior to activation by irradiation would be applicable to any virus in the last two paragraphs of section 3, the ordinary artisan would not reasonably predict success for maintaining D protein integrity of an inactivated poliovirus by adding MDP to the virus prior to irradiation due to the disparities in genome size, discussed separately by both Gayen et al. and Tobin et al.
Toyoda et al. (Journal of Molecular Biology. 1984 Apr 25; 174 (4): 561-585) teach that the poliovirus genome is approximately 7500 nucleotides in the paragraph bridging pages 561-562.
Table 2 of Strauss-Strauss (Microbiological Reviews. 1994 Sep; 58 (3): 491-562) show that the average genome size of alphaviruses is above 11,440 total nucleotides.
Therefore, alphavirus genomes are approximately 35% larger than poliovirus genomes.
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) refers not only to the expectation that prior art elements are capable of being physically combined, but also that the combination would have worked for its intended purpose. Application of the KSR requirement for "a finite number of identified predictable solutions" in a manner that places particular emphasis on predictability and the reasonable expectations of those of ordinary skill in the art would not have been evident for maintaining D protein integrity in irradiation-inactivated polioviruses upon the addition of MDP, as evidenced by instant Figures 2C and 6-9.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Allen can be reached at 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Shanon A. Foley/Primary Examiner, Art Unit 1671
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