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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/23/2025 has been entered.
Applicant’s reply and claim amendments have overcome the rejections under 35 USC §112(a), §112(b), and §102.
Claims 1 and 3-23 are pending and under consideration.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/23/2025 has been considered by the examiner.
Claim Objections
Claim 21 is objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim should refer to other claims in the alternative only. See MPEP § 608.01(n).
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 21 and 22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 21 contains the trademark/trade names, “ASO4”, “MF59”, “CpG1018”, and “Advax-2”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a specific adjuvant and, accordingly, the identification/description is indefinite.
Claim 22 is indefinite because it depends on cancelled claim 2.
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, 3-15, 17, and 19-23 are rejected under 35 U.S.C. 103 as being unpatentable over Darnell et al. (Transfusion. Oct. 2006; 46: 1770-1777, of record), Schneider et al. (Viruses. 2015; 7: 5875-5888, of record) and Weisehahn et al. (US 5,106,619, of record).
In “UV light treatment”, Darnell et al. teach a method of inactivating a live, human SARS-CoV by adding 15 µmol of a psoralen compound, as required by instant claims 1, 4, 6, 7, 23, and exposing the mixture to UV-A with a wavelength of 365 nm, as required by instant claims 8 and 9, resulting in inactivated virus to the limit of detection after 15 minutes in Figure 2B, as required by instant claims 1, 10, and 11. The stock of live, infectious SARS-CoV of Darnell et al. is at 105.33 TCID50/ mL, see “Virus and cells”, which is within the range of the virus quantity recited in instant claim 13. Instant claims 3 and 19 require that the instant inactivated whole virus comprises one or more SARS-CoV-2 variants of concern (VOC). The live SARS-CoV of Darnell et al., prior to inactivation, is a coronavirus that causes “life-threatening severe acute respiratory syndrome” in the first paragraph on page 1770, satisfying the “one or more variants”, recited in instant claims 3 and 19.
Darnell et al. do not teach that the that the psoralen compound is 4’aminomethyl-trioxsalen (AMT), recited in claim 5; or the radiation intensity ranges between 150 µW/cm2 to 1500 µW/cm2, as required in claim 12; or purifying the virus after UV exposure, recited in claim 15.
Schneider et al. teach adding to a live, infectious human MERS-CoV, 4’ aminomethyl-trioxsalen (AMT) psoralen and exposing the psoralen/ virus mixture to UV-A radiation at a measured energy level of 200 μW/cm2 to inactivate the virus, see section 2.2, as required by claims 5 and 12. In section 2.4, Schneider et al. teach purifying the psoralen-inactivated virus after UV-A exposure, as required by claim 15.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have used the 4’aminomethyl-trioxsalen (AMT) of Schneider et al. as the psoralen of Darnell et al. and exposing the psoralen/ virus mixture to UV-A radiation at a measured energy level of 200 μW/cm2 to inactivate the virus. 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 the 4’aminomethyl-trioxsalen (AMT) of Schneider et al. as the psoralen of Darnell et al. and exposing the psoralen/ virus mixture to UV-A radiation at a measured energy level of 200 μW/cm2 because both Darnell et al. and Schneider et al. teach inactivating human respiratory syndrome coronaviruses by exposure to a psoralen and UV-A at a wavelength of 365 nm for 5-30 minutes, see “UV light treatment” and Figure 2B of Darnell et al. and sections 2.2, 3.2 and Table 4 of Schneider et al., showing inactivation of all virus tested.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have purified the SARS-CoV of Darnell et al., as taught by Schneider et al., for utilizing them for molecular and/or immunological applications, see the abstract of Schneider 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 SARS-CoV of Darnell et al., as taught by Schneider et al., because both Darnell et al. and Schneider et al. teach inactivation of human respiratory syndrome coronaviruses by exposure to a psoralen and UV-A at a wavelength of 365 nm for 5-30 minutes, see “UV light treatment” and Figure 2B of Darnell et al. and sections 2.2, 3.2 and Table 4 of Schneider et al., showing inactivation of all virus tested.
Regarding the lack of degradation of the virus’s antigenic characteristics of psoralen-UV-A-inactivated SARS-CoV, as required in instant claims 1 and 17, Darnell et al. emphasize that virus inactivation methods…“must not compromise the stability of the proteins”…in noncellular blood products, in the last paragraph on page 1770. In the “Results” and “Discussion” sections, Darnel et al. mention denaturing and damage of proteins when SARS-CoV is inactivated with heat and solvent/detergent treatments, but no damage or denaturing was observed when SARS was inactivated upon the addition of 15 µmol of a psoralen compound and exposure to UV-A at a wavelength of 365 nm. In the paragraph bridging the columns on page 1775, Darnell et al. conclude, “The addition of intercalating agents, such as psoralen, may be required to increase the efficiency of UVA viral inactivation and may be appropriate for treatment of PLTs or red
cells”,…that are required to be safe for injection and “must not compromise the stability of the proteins”, in the last paragraph on page 1770.
Schneider et al. specifically teach AMT-UV-A-inactivated viruses produce polyclonal antibodies equally as well as untreated virus, denoting intact inactivated virus that can be used in vaccine development, see sections 2.4 and 2.5. In sections 3.3-3.6, Schneider et al. specifically teach that viral RNA retains molecular integrity, maintains virus surface epitopes, and retains receptor binding, after AMT treatment for Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae virus representatives. In the second full paragraph on page 5885, Schneider et al. conclude that “[t]he method was effective at inactivating…Corona-” viruses. In the third paragraph on page 5885, Shneider et al. conclude that, “the surface proteins of the inactivated viruses are intact and correctly oriented, allowing full interactions with cells and protein complexes. This will allow viruses inactivated by this method to be used in vaccine development.”
Weisehahn et al. claim a viral vaccine produced by exposing a live virus (including coronavirus, listed in the Table in column 3) to long wavelength ultraviolet radiation and an inactivating furocoumarin, AMT (see column 4, lines 14-58), in an aqueous solution for a time period sufficiently long to render the virus non-infectious but not long enough to degrade its antigen characteristics, see claim 1, as required by instant claim 1.
Therefore, one of ordinary skill in the art prior to the effective filing date would have had a reasonable expectation of success for rendering any coronavirus non-replicative, but undegraded and the virus’s antigenic characteristics intact, in the method of Darnell et al., Schneider et al., and Weisehahn et al., especially since the parameters used to inactivate the coronavirus of SARS of Darnell et al., the coronavirus of Weisehahn et al., and the MERS-CoV of Schneider et al., are the same steps and overlapping materials.
Recitation of "vaccine" in instant claims 1, 17, and 20-22 and the “immunogenic composition, recited in claim 23, are intended uses and not structural limitations. Darnell et al., Schneider et al., and Weisehahn et al. all separately teach a psoralen/ UV-A-inactivated coronavirus that possesses the same characteristics as the claimed psoralen/ UV-A-inactivated coronavirus. Therefore, applicant’s inactivated coronavirus, described in product-by process terms, reasonably appears to encompass inactivated coronaviruses that are indistinguishable from the inactivated coronavirus of Darnell et al., Schneider et al., and Weisehahn et al. 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.
Neither Darnell et al. nor Schneider et al. teach the temperature is maintained at 4 °C during UV exposure, as required by instant claim 14 or adding an alum adjuvant, as required by instant claims 20, 21, or a pharmaceutically acceptable adjuvant, recited in instant claim 23.
Weisehahn et al. teach that the temperature for the irradiation is between 0°C to 10°C, see column 6, lines 51-54, and specifically teaches 4°C, see column 11, lines 5-6, for example, as required by instant claim 14. In example 2, Weisehahn et al. teach combining the psoralen-UV-A-inactivated virus with an aluminum hydrogel adjuvant, as required by instant claims 20, 21, and 23.
One of ordinary skill would have been motivated to have maintained the irradiation step of Darnell et al. and Schneider et al. between 0°C to 10°C, as taught by Weisehahn et al., to maintain stability during radiation with a reasonable expectation of success. One of ordinary skill in the art prior to the effective filing date would have been motivated to have added the aluminum hydrogel adjuvant to the inactivated coronavirus of Schneider et al. to enhance an immune response.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Darnell et al., Schneider et al., and Weisehahn et al. as applied to claims 1, 3-15, 17, and 19-23 above, and further in view of Strakhovskaya et al. (Laser Physics Letters. August 2020; 17, of record).
See the teachings of Darnell et al., Schneider et al., and Weisehahn et al. above. None of the references mention SARS-CoV-2, as required.
Strakhovskaya et al. do, see the abstract and section 4.
One of ordinary skill in the art prior to the effective filing date would have been motivated to have inactivated SARS-CoV-2 of Strakhovskaya et al. with the method of Darnell et al., Schneider et al., and Weisehahn et al. to produce an inactivated SARS-CoV-2 vaccine. One of ordinary skill in the art prior to the effective filing date would have had a reasonable expectation of success for producing an inactivated SARS-CoV-2 with the method of Darnell et al., Schneider et al., and Weisehahn et al. because Strakhovskaya et al. teach successful inactivation of SARS-CoV-2 with a psoralen and exposure to UV-A, see section 4.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Darnell et al., Schneider et al., and Weisehahn et al. as applied to claims 1, 3-15, 17, and 19-23 above, and further in view of Kitazato et al. (USPgPub 2002/0169306), of record.
See the teachings of Darnell et al., Schneider et al., and Weisehahn et al. above. None of the references teach purifying the coronavirus/ psoralen mixture by sucrose gradient centrifugation.
Kitazato et al. teach purifying the virus culture by sucrose gradient centrifugation, see paragraph [0303].
One of ordinary skill in the art prior to the effective filing date would have been motivated to have purified the coronavirus/ psoralen mixture of Darnell et al., Schneider et al., and Weisehahn et al. by sucrose gradient centrifugation, as taught by Kitazato et al., to recover and purify virus.
Response to Arguments
In the reply to the rejection of record, applicant argues that Darnell et al. adds a psoralen compound with molecular weight of 186.16 (Sigma-Aldrich Inc.) to SARS-CoV diluted in BSA-PBS, PBS or DMEM solution (final concentration 15µmol/L), which results in a concentration of 2.7924 µg/mL, which is lower than the claimed psoralen of 5-150 µg/mL concentration (claim 7).
Applicant’s arguments and a review of Darnell et al. have been fully considered. Darnell et al. is silent regarding the molecular weight of the psoralen compound used to inactivate SARS-CoV-2. Therefore, the calculations provided by applicant are unsupported. The final concentration of 15 μmol/L of a psoralen added by Darnell et al. falls within the quantity of psoralen recited in instant claims 1, 4, 6, 7, and 23. None of instant claims 1, 4, 6, 7, and 23 recite a specific psoralen, much less a molecular weight of a psoralen. Even assuming arguendo that applicant’s calculations are supported in the teachings of Darnell et al., Schneider et al. teach inactivating a respiratory syndrome coronavirus by adding 4'aminomethyl-trioxsalen (AMT) psoralen (recited in instant claim 5) to a final concentration of 10 µg/mL prior to exposing the psoralen/ virus mixture to UV-A radiation, see section 2.2. Weisehahn et al. specifically teach inactivating a coronavirus (listed in the Table in column 3), by adding 4'aminomethyl-trioxsalen (AMT) and/or 8-methoxypsoralen (8-MOP) and/or 4,5’,8-trimenthylpsoralen (TMP) psoralen (all recited in instant claim 5) to a final concentration ranges between 0.5 µg/mL to 100 µg/mL in column 4, lines 14-16, 30-44, prior to exposing the psoralen/ virus mixture to UV-A radiation in column 6, lines 47-49. Also see claims 1, 7-10, and 12.
MPEP § 2144.05 teach:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)
In the instant case, Darnell et al., Schneider et al., and Weisehahn et al. teach the quantity of psoralen concentrations necessary to inactivate coronaviruses with sufficient specificity.
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to have modified the psoralen amounts of Darnell et al., Schneider et al., and Weisehahn et al., to 5-150 µg/mL or 10-50 µg/mL, recited in instant claims 6 and 7, respectively, since there appears to be no evidence of criticality of the instant psoralen concentrations because the concentrations of psoralen ranges between any quantity of psoralen, encompassed by instant claims 1, 3-5, 8-23 or between 5-150 µg/mL or 10-50 µg/mL, recited in instant claims 6 and 7. In addition, paragraph [0018] of the instant published disclosure, USPgPub 2022/0168411 (of record), states: “the solubility of the psoralen can be increased to about 50 μg/ml, or higher”. Instant paragraph [0016] states that the psoralens may be present in an amount ranging between 1-200 μg/ml.
Applicant states that the UVA light source used in Darnell et al,. emitted at 2133 µW/cm², which is much higher than claimed radiation intensity of 150 µW/cm² to 1500 µW/cm² (claim 12).
Applicant’s arguments and the teachings of Darnell et al. have been fully considered. The first paragraph on page 7 of the June 26, 2025 rejection states that Darnell et al. do not teach “the radiation intensity ranges between 150 µW/cm² to 1500 µW/cm², as required in claim 12”. However, this limitation is satisfied by the teachings of Schneider et al. Schneider et al. teach adding to a live, infectious human MERS-CoV, 4’aminomethyl-trioxsalen (AMT) psoralen and exposing the psoralen/ virus mixture to UV-A radiation at a measured energy level of 200 μW/cm2 to inactivate the virus, see section 2.2, as required by claims 5 and 12.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have exposed the psoralen/ coronavirus mixture of Darnell et al. to UV-A radiation at a measured energy level of 200 μW/cm2, taught by Schneider et al., to inactivate the virus. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have exposed the psoralen/ coronavirus mixture of Darnell et al. to UV-A radiation at a measured energy level of 200 μW/cm2, taught by Schneider et al. because both Darnell et al. and Schneider et al. teach inactivating human respiratory syndrome coronaviruses by exposure to a psoralen and UV-A at a wavelength of 365 nm for 5-30 minutes, see “UV light treatment” and Figure 2B of Darnell et al. and sections 2.2, 3.2 and Table 4 of Schneider et al., showing inactivation of all viruses tested.
Applicant states that while Darnell et al. starts with 106.33 TCID₅₀/ mL virus stock under "Virus and cells", Darnell et al.’s SARS sample was incubated in DMEM with supplements, and then filtered and diluted in BSA, PBS and DMEM. Therefore, it is unclear if Darnell's final SARS concentration falls within the claimed range Claim 13 requires a coronavirus concentration in medium to be 1x10⁵ to 1x 10¹² pfu/mL. Applicant argues that neither Schneider et al. nor Weisehahn et al. teach the requisite limitation.
The teachings of Darnell et al. and the requirements of instant claim 13 have been considered, but are found unpersuasive. Instant claim 13, incorporating all of the limitations from claims 1 and 4, from which claim 13, depends, requires: the inactivating psoralen compound is added to a medium containing said live coronavirus, wherein said live coronavirus concentration in the medium is 1x10⁵ to 1x 10¹² pfu/mL. As applicant states, Darnell et al. starts with 106.33 TCID₅₀/ mL virus stock under "Virus and cells". This teaching is followed by a description of further processing, i.e., collection, pooling and centrifugation of supernatants, followed by filtration through a 0.22 µm filter unit, “and diluted 10-fold in bovine serum albumin (BSA; Sigma-Aldrich Inc., St. Louis, MO) solutions, phosphate-buffered saline (PBS; Biosource International), or” (not “and”, as stated by applicant) “DMEM without supplements for inactivation.” A 10-fold dilution of 106.33 TCID₅₀/ mL virus stock is 105.33 TCID₅₀/ mL virus stock, meeting the limitations recited in instant claim 13. The stock of live, infectious MERS-CoV of Schneider et al. is at 10⁶.⁹ TCID₅₀/ mL, see section 2.2, which is also encompassed by virus quantity recited in instant claim 13. In column 4, lines 50-51 and column 7, lines 4-6, Weisehahn et al. teach virus concentration prior to inactivation ranges between 106 to 1011 pfu/ml, also encompassed by virus quantity recited in instant claim 13. Therefore, the starting concentration ranges of virus prior to inactivation by psoralen and UV-A exposure achieves a consensus in the art prior to the instant effective filing date as ranging between 105 to 1011, as required in instant claim 13.
Applicant points out that Schneider et al teach inactivation of a MERS-CoV at 6000µW/cm² in Table 4, which is much higher than claimed UVA intensity of 150 µW/cm² to 1500 µW/cm² (claim 12).
Applicant’s arguments and a review of the teachings of Schneider et al. have been fully considered, but are found unpersuasive. The 6000µW/cm² in Table 4 of Schneider et al. to inactivate MERS is the measurement of the total accumulated energy delivered to a surface per unit area over a period of time. Section 2.2, (“Virus Inactivation by Psoralen”) of Schneider et al. explains that plates comprising 106.4 TCID50 infectious MERS viruses were exposed to UV-A radiation at 365 nm for 0, 2, 5, 10, 20, 30, 40, 50, or 60 minutes at a measured energy level of 200 µW/cm2. To calculate the requisite exposure time (selected from 0, 2, 5, 10, 20, 30, 40, 50, or 60 minutes) required to inactivate MERS upon exposure to a measured energy level of 200 µW/cm2 to arrive at the total accumulated energy of 6000 µW/cm² in Table 4, is:
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Therefore, the total energy dose required, but not claimed, to inactivate a coronavirus in an exposure time ranging between 5-30 minutes (recited in instant claim 10) in the presence of a psoralen and UV-A radiation at 365 nm (recited in instant claim 9) at a UV radiation intensity of 200 µW/cm2 (encompassed within the range of instant claim 12) would equal 6000 µW/cm², listed in Table 4 of Schneider et al.
Applicant points out that the viral vaccine of Weisehahn et al., produced by exposing live virus to long wavelength ultraviolet radiation and an inactivating furocoumarin, AMT (in column 4, lines 14-58), in an aqueous solution for a time period sufficiently long to render the virus non-infectious but not long enough to degrade its antigen characteristics, is related to feline infectious peritonitis.
Applicant’s arguments and a review of Weisehahn et al. have been fully considered, but are found unpersuasive since the feline infectious peritonitis of Weisehahn et al. is a representative of highly pathogenic coronaviruses that cause systemic infection, which are phenotypes of MERS (of Schneider et al.), SARS (Darnell et al.), and SARS-CoV-2 (Strakhovskaya et al.).
Applicant argues that Darnell et al. is focused on plasma protein function instead of antigenicity after inactivation of psoralen-UV-A-inactivated SARS-CoV, pointing to page 1770, discussing preservation of blood protein functions versus preservation of virus antigenicity. Applicant asserts that Darnell et al.’s teaching that heat and solvent/detergent results in denaturing an damage of proteins is contradicted in the last paragraph on page 1775.
Applicant’s arguments have been fully considered, but are found unpersuasive. The quoted passage on page 1770 of Darnell et al., emphasizing maintenance of protein stability in virus inactivation methods pertains to all proteins in the composition. The first sentence under “Heat inactivation of SARS-CoV” states (emphasis underlined for convenience):
Heat may inactivate viruses by denaturing the secondary structures of proteins and thereby may alter the conformation of virion proteins involved in attachment and replication within a host cell.
In the paragraph bridging pages 1775-1776, Darnell et al. state (emphasis underlined for convenience):
S/D methods are not used for inactivation of viruses in cellular blood components because S/D treatment damages cell membranes.27 The S/D method causes a disruption of the structural integrity of lipid-enveloped viruses.
Therefore, Darnell et al. emphasize maintaining protein stability in virus inactivation methods, pertaining to all proteins in the composition.
Applicant asserts that selection of inactivation conditions are critical in psoralen-UVA inactivation and that inactivation conditions may vary among virus members of the same family, as evidenced by Schneider et al. Applicant argues that none of the references contain any evidence to show full inactivation of claimed coronavirus species under claimed inactivation conditions.
Applicant’s arguments have been fully considered, but are found unpersuasive. The dose of any psoralen or AMT and length of ultraviolet or UV-A exposure time required are not recited in instant claims 1, 3-5, 8, 9, and 12-23. The specific dose of any psoralen or AMT is 5-150 µg/mL or 10-50 µg/mL in claims 6 and 7, respectively, and length of ultraviolet or UV-A exposure time required in instant claims 10 and 11 ranges from 5-30 minutes and 5-15 minutes, respectively. Darnell et al. teach a method of inactivating a live, human SARS-CoV by adding 15 µmol of a psoralen compound and exposing the mixture to UV-A, resulting in inactivated virus to the limit of detection after 15 minutes in Figure 2B. Schneider et al. teach inactivating MERS-CoV with the addition of 10 µg/mL of AMT and exposure to UV-A radiation for 0, 2, 5, 10, 20, or 30 minutes in section 2.2. Weisehahn et al. specifically teach inactivating a coronavirus (listed in the Table in column 3), by adding 4'aminomethyl-trioxsalen (AMT) and/or 8-methoxypsoralen (8-MOP) and/or 4,5’,8-trimenthylpsoralen (TMP) psoralen (all recited in instant claim 5) to a final concentration ranges between 0.5 µg/mL to 100 µg/mL in column 4, lines 14-16, 30-44, prior to exposing the psoralen/ virus mixture to UV-A radiation in column 6, lines 47-49. Also see claims 1, 7-10, and 12. Therefore, the conditions required for psoralen-UV-A inactivation of a coronavirus that causes severe acute respiratory syndrome in humans was established in the art prior to the instant effective filing date.
One of ordinary skill in the art prior to the effective filing date would have been motivated to have inactivated SARS-CoV-2 of Strakhovskaya et al. with the method of Darnell et al., Schneider et al., and Weisehahn et al., to produce an inactivated SARS-CoV-2 vaccine. One of ordinary skill in the art prior to the effective filing date would have had a reasonable expectation of success for producing an inactivated SARS-CoV-2 with the method of Darnell et al., Schneider et al., and Weisehahn et al. because Strakhovskaya et al. teach successful inactivation of SARS-CoV-2 with amotosalin psoralen and exposure to UV-A for 3-6 minutes, see section 4.
The parameters used to inactivate the coronavirus of Weisehahn et al. and the MERS-CoV by Schneider et al. are the same steps and overlapping materials. In example 2, Weisehahn et al. teach combining the psoralen-UV-A-inactivated virus with an aluminum hydrogel adjuvant, and claim a vaccine comprising a virus inactivated by contact with a psoralen compound and exposure to ultraviolet radiation and a preselected concentration of an inactivating furocoumarin for a time period sufficiently long to render the virus non-infectious but not long enough to degrade its antigen characteristics in claims 1 and 9.
Applicant argues that none of Darnell et al., Schneider et al., and Wiesenhahn et al. offer any evidence to support a method that is capable of producing a fully inactivated vaccine that protects against SARS-CoV-2, human coronavirus OC43, human coronavirus HKU1 or SARS-CoV. The references fail to demonstrate the antigenicity of the inactivated viruses or protection of the psoralen UVA inactivated vaccines. Applicant points to Sutjipto et al. (cited in the IDS) failing to fully inactivate SIV and protection against mucosal infection, contrasting with two additional articles, provided in the IDS, showing protective efficacy of claimed psoralen-Inactivated SARS-CoV-2.
Applicant’s arguments have been fully considered, but are found unpersuasive. Recitation of "vaccine" in instant claims 1, 17, and 20-22 and the “immunogenic composition, recited in claim 23, are intended uses and not structural limitations. Darnell et al., Schneider et al., and Weisehahn et al. all separately teach a psoralen/ UV-A-inactivated coronavirus that possesses the same characteristics as the claimed psoralen/ UV-A-inactivated coronavirus. Therefore, applicant’s inactivated coronavirus, described in product-by process terms, reasonably appears to encompass inactivated coronaviruses that are indistinguishable from the inactivated coronavirus of Darnell et al., Schneider et al., and Weisehahn et al. 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.
In instant claim 17, where the vaccine is capable of stimulating antibody and T cell immune responses, does not actually require the vaccine to be used in that way. See Catalina Mktg. Int'l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801, 809 (Fed. Cir. 2002) (“[T]he patentability of…composition claims depends on the claimed structure, not on the use or purpose of that structure.”).
Even if the instant claims required stimulating antibody and T cell immune responses and protective efficacy, one of ordinary skill in the art prior to the effective filing date would have had a reasonable expectation of success for rendering any coronavirus non-replicative, but with conserved surface protein structures. In the method of Schneider et al., inactivation is achieved for all virus tested in section 3.2 and Table 4 and the inactivated MERS-CoV produce polyclonal antibodies equally as well as untreated virus, in sections 2.4, 2.5, and the second full paragraph on page 5885. Therefore, the relevant structural similarity between the psoralen-UV-A inactivated virus and the un-inactivated live virus, required to retain antigenicity to induce an immune response, is established by Schneider et al. The data provided by Schneider et al. supports preservation of antigenic integrity of a viral surface after psoralen-UV-A inactivation, as discussed in the paragraph bridging pages 5876- 5877.
Regarding applicant’s assertion of unpredictability for lack of protective efficacy of a psoralen-UV-A-inactivated SIV, as evidenced by Sutjipto et al. In the second paragraph under “Psoralen-UV-light inactivation of the virus”, Sutjipto et al. discuss executed procedures ensuring that the psoralen-UV-A-inactivated SIV was free from residual infectious particles. There is no evidence that the psoralen-UV-A-inactivated SIV vaccine of Sutjipto et al. was not fully inactivated. Protective efficacy does not solely rely on the inactivated material administered, especially with respect to lentiviruses (not claimed). For example, Shearer et al. (Medicine Reports. 2011 Jun 1; 3:12) review an inactivated SIV that demonstrated protective efficacy against SIV infection in macaques. However, it was discovered that the promising protective efficacy was due to macaque cell antigens present on the surface of the virus particles produced in human cell cultures instead of SIV-specific immune responses, see the abstract and introduction.
In contrast, Weisehahn et al. claim a vaccine comprising a virus inactivated by contact with a psoralen compound and exposure to ultraviolet radiation and a preselected concentration of an inactivating psoralen for a time period sufficiently long to render the virus non-infectious but not long enough to degrade its antigen characteristics in claims 1, 7-9, 10, and 12, with demonstrated protective efficacy against virulent challenge after immunization with corresponding psoralen-UV-A-inactivated viral vaccines in the working examples bridging columns 7-22. In column 22, lines 35-45, Weisehahn et al. conclude, “ viruses inactivated with furocoumarins and ultraviolet radiation in the substantial absence of oxygen and other oxidizing species retain their immunogenicity and are suitable as the immunogenic substance in vaccines against a number of virally-induced diseases. The inactivated viruses of the present invention are non-infectious and safe when administered to a host for vaccination, yet display enhanced antigenic integrity when compared to vaccines inactivated in the presence of oxygen.”
Schneider et al. specifically teach that viral RNA retains molecular integrity, maintains virus surface epitopes, and retains receptor binding, after AMT treatment for Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae virus representatives. In the second full paragraph on page 5885, Schneider et al. conclude that “[t]he method was effective at inactivating…Corona-” viruses. In the third paragraph on page 5885, Shneider et al. conclude that, “the surface proteins of the inactivated viruses are intact and correctly oriented, allowing full interactions with cells and protein complexes. This will allow viruses inactivated by this method to be used in vaccine development.”
Under “Anti-RNA Virus”, Ren et al. (Frontiers in Pharmacology. 2020 Sep 4; 11: 571535) review a number of effective psoralen-inactivated vaccines, including Dengue-1 and influenza. Ren et al. conclude, “psoralen has the characteristics of retaining the three-dimensional structure of the virus, preserving immunogenicity, which is conducive to vaccine production. Therefore, it is anticipated that psoralen could be used as an agent to treat or prevent SARS-CoV-2 and has potential application value in the preparation of related vaccines.” Given the protective immunizations of psoralen-UVA-inactivated Herpes-, Orbi-, and Rhabodo- viruses, demonstrated in the working examples of Weisehahn et al., and the psoralen-inactivated vaccines of Dengue-1 and influenza, discussed by Ren et al., protective efficacy of the psoralen-UV-A-inactivated SARS-CoV-2 in the references provided in the 12/23/2025 IDS, would not have been unexpected to one of ordinary skill in the art prior to the instant effective filing date.
Conclusion
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/Shanon A. Foley/ Primary Examiner, Art Unit 1671