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 was filed in this application after a decision by the Patent Trial and Appeal Board, but before the filing of a Notice of Appeal to the Court of Appeals for the Federal Circuit or the commencement of a civil action. 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examination under 37 CFR 1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the appeal has been withdrawn pursuant to 37 CFR 1.114 and prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant’s submission filed on April 29th, 2026 has been entered.
All previous objections and rejections not reiterated herein were overcome by claim amendments and arguments, filed April 29th, 2026, have been fully considered and found persuasive. As such all objections and rejections not reiterated herein have been withdrawn.
Election/Restrictions
Claims 8, 12, 21, 28, 48, 65 – 71, 73 – 75, and 77 are currently pending in the application. However, due to a restriction requirement dated September 20th, 2021, claims 71, and 73 – 75 are withdrawn from further consideration and claims 8, 12, 21, 28, 48, 65 – 70, and 77 are being examined on the merits herein.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 8, 12, 21, 28, 48, 65 – 70, and 77 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (WO 2011/119759 A1; cited on the IDS dated May 29th, 2020), in view of Tan et al. (“Intranasal Administration of TLR2 agonist Pam2Cys provides rapid protection against influenza in mice,” Molecular Pharmaceutics, 2012, Vol. 9, pp 2710-2718; cited on the IDS dated May 29th, 2020), Djupesland (“Nasal drug delivery device: characteristics and performance in a clinical perspective-a review,” Drug Deliv. And Transl. Res. 2013, Vol. 3, pp 42-62; cited in the office action dated February 9th, 2022), Chaturvedi et al. (“A review on mucoadhesive polymer used in nasal drug delivery system.” J. Adv. Pharm. Tech. Res. 2011, Vol. 2, Issue 4, pp 215-222; cited in the office action dated February 9th, 2022), Cheng et al. (“Characterization of Nasal spray pumps and deposition pattern in a replica of the human nasal airway,” J. Aerosol Medicine, 2001, Vol. 14, No. 2, pp 267-280; cited in the office action dated April 26th, 2023), Bogoch et al. (“Diagnosis of influenza from lower respiratory tract sampling after negative upper respiratory tract sampling.” Virulence 2013, Vol. 4, No. 1, pp 82-84; cited in the office action dated April 26th, 2023), and Rathananand et al. (“Preparation of mucoadhesive microspheres for nasal delivery by spray drying,” Indian J. Pharm. Sci. 2007, 69 (5) 651-657; cited in the office action dated April 26th, 2023).
Regarding claims 8, 12, 21, 28, 48, 65 – 70, and 77, Wu et al. teach TLR2 agonists with a general formula of
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, which encompassing Pam2Cys derivatives. See, particularly paragraphs [0009] to [0014]. Wu et. al. expressly disclosed examples include compounds having Pam2Cys moieties, such as compound 48:
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, and compounds having Cys-Ser peptide with polyethylene glycol moiety, such as compound 88:
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, which has superior TLR2 agonistic activity, See, table I, pages 163-178. Wu et. al. further discloses pharmaceutical composition comprising the TLR2 agonists, or pharmaceutical acceptable salts, solvate, N-oxide, prodrugs thereof, and method of using the same for treating infectious disease, particularly, those caused by viruses, such as rhinovirus, coronavirus, influenza. See, particularly, paragraph [000179].
Wu et. al. teach that the infectious disease also include bacterial infection, fungal infections, such as tuberculosis, pneumocytis carnii. See, particularly, paragraph [00180]. Wu et. al. teach that the daily dosage of the compounds may be in the range of 0.05 µg/kg to100 mg/kg per body weight. Wu et. al. teach that the dosage form may be oral, parenteral, topical, or directly to respiratory tract. Moreover, Wu et. al. teach that for inhalation administration, the composition may be in the form of aerosol, which may be a solution or suspension, or by metered dose inhaler (MDI), other known device known in the art. See, particularly, paragraphs [000186] to [000206]. Particularly, Wu et. al. teach that the pharmaceutical composition is formulated for intravenous administration, intravitrial administration, intramuscular administration, oral administration, rectal administration, inhalation, nasal administration, topical administration, ophthalmic administration or otic administration. Wu et. al. teach that other embodiments of such pharmaceutical compositions, the pharmaceutical compositions is in the form of a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a solution, an emulsion, an ointment, eye drop or ear drop. See. paragraph [00026].
However, Wu et. al. do not teach expressly the compound of elected species INNA-006, characterized by the Pam2Cys-Ser-(CH2-CH2-O)12-glycinaminde, which differ from the compound of Wu in the chain lengths of the fatty acids (C12 vs C16) and PEG, and the C-terminal (glycinamide vs CH2COOH). See claim 48. Furthermore, Wu et. al. do not teach expressly the particle size herein recited for intranasal administration. See claim 8.
Nevertheless, Tan et. al. teach that Pam2Cys is a synthetic analogue of the lipid component of MALP-2 and has been shown as an agonist for TLR2. See, the Introduction section at page 2710. Tan et. al. teach that in its native form Pam2Cys is insoluble in aqueous solution. Tan et. al. teach that the conjugation of Pam 2Cys to polyethylene glycol through a method known in the art to obtain a pegylated Pam2Cys, is readily soluble in saline and can be administered intranasally to respiratory tract against influenza infection. Tan et. al. demonstrated that the efficacy of the conjugate against distinct strains of influenza and it’s potential against other respiratory pathogens. Tan et. al. teach that the conjugate has the PEG moiety terminated with glycyl amide
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. See, particularly, the abstract, page 2711, Figure 1; page 2712, the left column, the Results section. Tan et. al. teach that the pegylated Pam2Cys act as an immunostimulant by attracting neutrophils and macrophages and inducing secretion of IL-2, IL-6, IL-10, IFN-γ, MCP-1 and TNF-α. Tan et. al. teach that these change provide increase resistance against influenza A virus challenge and other benefit as well. See, the abstract.
Djupesland reveals that intranasal drug delivery has been old and well-known in the art and many dosage forms and delivery devices, including drops delivered with pipette, are known in the art, each with different characteristics suitable for various situations. See, particularly, the abstract at page 42, 46-51, particularly, table 1 at page 47. Single dosed pipettes is commonly used in the art. (page 46, the right column). Furthermore, Djupesland teach that the nasal cavity is part of upper respiratory tract. See, particularly, page 44, the figures.
Chaturvedi et. al. teach that mucoadhesive polymer in nasal delivery system provides many advantages, such as promoting dosage form residence time in the nasal cavity as well as improving intimacy of contact with absorptive membranes of the biological system. See, the abstract. Chaturvedi et. al. disclose one of limitation of nasal drug delivery is that there could be mechanical loss if the dosage form into the other part of the respiratory tract like lung. See, page 215, the last paragraph bridging to page 216. Chaturvedi et. al. teach that mucoadhesive polymers have been used in various dosage forms of nasal delivery drugs, including liquid, spray and gels. See, page 219.
Cheng et. al. teach that the droplet size is closely related to the delivery efficacy to nasal cavity. Cheng et. al. teach that the efficacy increases with the particle size. And Cheng et. al. teach that from 1 µm to 10µm, 10 µm is the best. See, Figure 4 at page 271. Cheng et. al. teach that other factors affecting the efficacy including the spray devices and the angles of spray. See, particularly, page 279.
Bogoch et. al. teach that most influenza infections affect the upper respiratory tract,
while lower tract infection typically represents extension from upper airways. See, the introduction section page 82.
Rathananand et. al. reveal that it has been known in the art that the ideal microsphere particle size requirement for nasal delivery should range from 10 to 50 µm as smaller particles than this will enter the lungs; even though a significant portion of small particles are also deposited in the nose. See, page 4 of attached copy.
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, at the time before the effective filing date of the claimed the invention, to make the Pam2Cys –pegylated conjugation herein with the particular PEG moiety employed herein, i.e., through one serine, 28 units of ethylene glycol and the particular glycyl amide terminal group and to use it as a TLR2 agonists for treating and/or preventing conditions associated with viral or bacterial infection, including influenza infection, by administering the composition directly to respiratory tract, e.g., through intranasal administration, particularly for subject with upper respiratory infection.
A person of ordinary skill in the art would have been motivated to make the Pam2Cys –pegylated conjugation herein with the particular PEG moiety employed herein, i.e., through one serine, 28 units of ethylene glycol and the particular glycyl amide terminal group and to use it as a TLR2 agonists for treating and/or preventing conditions associated with viral or bacterial infection, including influenza infection, by administering the composition directly to respiratory tract, e.g., through intranasal administration, particularly for subject with upper respiratory infection because the glycyl amide has been shown as suitable terminating group for pharmaceutical utility, and Pam2Cys has been an old and established TLR2 agonist suitable for pharmaceutical application. Further, adjust the length of PEG for hydrophilicity or aqueous solubility of the compounds would have been a matter of optimization of result affecting parameters, and would have been obvious to one of ordinary skill in the art. Note, where 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).
The nasal administration, such as drops delivered with pipette or dropper, or nasal spray would not normally deliver the drug to lower respiratory tract and it would have been with the purview of ordinary skill in the art to avoid the known mechanical loss of drug to lower respiratory tract. As to the particular particle or droplet size, note, make the particle or droplet size more than 10 µm would have been obvious as larger droplet size would lead to higher efficacy of delivery and it has been known that ideal particle size for nasal delivery should range from 10 to 50 µm. Further, optimization of particle or droplet size for an optimal delivery efficacy through routine experimentation would have been within the purview of ordinary skill in the art. Furthermore, one of ordinary skill in the art would have been motivated to treating influenza infection by intranasal administration because the influenza mostly infect upper respiratory tract and intranasal administration has been known for upper respiratory tract delivery and has been known for treating influenza infection.
As to claim 8, such an intranasal treatment would have reasonably been expected to suppressing the viral infection from further development into lower respiratory tract, such as lung.
For claim 21, it would have been with the purview of ordinary skill in the art to administer effective amounts of the drug with the known method, dropping, in a proper way so to avoid leak the liquid into the lung, such as properly arrange patient’s nasal and/or head position to avoid mechanical loss of the nasal dosage from nasal cavity.
As to claim 66, note it would have been obvious to use a mucoadhesive polymer in the liquid drop because the mucoadhesive polymer would promote dosage form residence time in the nasal cavity, overcome mechanical loss, and improving the efficacy of drug delivery.
For claim 65, making a unit dose dispenser, Single dosed pipettes, would have been obvious as it has been a common practice in the art for making a single dosed pipette for nasal delivery.
As to claim 67, it would have been within the purview of ordinary skill in the art to realize an intranasal administration and to avoid any loss of the drug to lower respiratory track with known method, such as adjusting the particle or droplet size, devices which could control the particle or droplet size and proper method for using such device as suggested by Cheng et. al. and Rathananand et. al.
Response to Arguments
Applicant's arguments and claim amendments filed April 29th, 2026, in regards to the prior art rejection of instant claims 8, 12, 21, 28, 48, 65 – 70, and 77, have been fully considered but they are not persuasive.
Applicant argues that it was surprising that the localized intranasal administration of a TLR2 agonist can prevent a viral infection from progressing to the lung. (see applicant’s remarks page 8 paragraph 3).
The examiner contends that there is no showing of in the remarks, specification or affidavit submitted September 5th, 2023 of surprising or unexpected results. The examiner contends that must be a comparison between the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). See MPEP 716.02(e). Moreover, any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). See MPEP 716.02.
Applicant considers that the Patent Trial and Appeal Board (PTAB) erred in their Decision at least insofar as the relevant teaching of Tan et. al. See applicant’s remarks page 8 paragraph 4. Specifically, applicant argues that the reference of Tan et.al. teaches away from limiting the administration to the nose. See applicant’s remarks page 8 paragraph 4 and page 9 paragraph 1. Furthermore, the applicant argues that none of the prior art references of record teach intranasal administration at the particle size of greater than 10 µm as recited in claim 8. See applicant’s remarks page 8 paragraph 1.
Once again the examiner contends that the Patent Trial and Appeal Board (PTAB) is the controlling body in this decision. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Moreover, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant points out that the commercial success of the instant application invention as a secondary objective indicia of nonobviousness by successfully fund raising US$ 22.4m towards a Phase 2 clinical trial (POSITS study). See applicant’s remarks page 10 paragraph 3.
The examiner contends that the precuring of grant money for clinical trials it not evidence of commercial success. In particular the examiner contends that objective evidence of commercial success may be given less weight if the record shows that the applicant or patent owner has a strong market power or blocking patent depending on the facts of record. See MPEP 716.01(c ) IV. Moreover, the examiner contends that the applicant who is asserting commercial success to support its contention of nonobviousness bears the burden of proof in establishing commercial success. See MPEP 716.03(I). Thus the examiner contends that the applicant must provide hard evidence of commercial success is commensurate in scope with the claims. See MPEP 716.03(a)(I). Furthermore, the examiner contends that the commercial success alleged is require to be a result of the invention claimed, in a marketplace where the consumer is free to choose on the basis of objective principles, and that such success is not the result of heavy promotion or advertising, shift in advertising, consumption by purchasers normally tied to applicant or assignee, or other business events extraneous to the merits of the claimed invention, etc. In re Mageli, 470 F.2d 1380, 176 USPQ 305 (CCPA 1973). See MPEP 716.03(b)(I).
Conclusion
Claims 8, 12, 21, 28, 48, 65 – 70, and 77 are rejected.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 DAWANNA S WHITE whose telephone number is (703)756-4687. The examiner can normally be reached 7:00 am - 5:00 pm [EST] M - Th.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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