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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 June 6, 2025, has been entered.
Priority
Applicants claim for priority to a provisional application 62/951,523 is acknowledged. The effective filing date for claims 45, 119-120, and 122-124 is Dec. 20, 2019.
Claim Status
In response filed on June 6, 2025, Applicant have amended claims 45 and canceled claims 1-44, 46-118, 121, and 125-128.
Applicant election without traverse of Group I (Claims 45, 119-120, and 122-124) and species (A) inhaled therapeutics polypeptides and alpha-1-antitrypsin polypeptide SEQ ID NO: 3 in the reply filed on January 20, 2023, is acknowledged.
Currently, claims 45, 119-120, and 122-124 are under examination in this application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on Jan. 2, 2025, and June 6, 2025, are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 45, 119-120, and 122-124 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.
This rejection is a new rejection necessitated by amendments to the claims.
Regarding claim 45 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of “the inhaled therapeutic polypeptide” is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: The alternatives are not part of the same art-recognized class and are not considered to be functionally equivalent. The alternatives fail to share a single functional similarity. For example, the polypeptide Sperm-associated antigen 1 (SPAG1)(i.e. ATP/GTP-binding site); and the polypeptide Armadillo repeat containing protein 4 polypeptide (i.e. Beta-catenin Wnt signaling pathway or tumor suppressor). The alternatives also fail to have a common use. For example, a sperm associated polypeptide would be associated with sperm, while Armadillo repeat containing protein 4 polypeptide is associated with many cancers.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 45, 119-120, and 122-124 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Gonda et al (U.S. Patent 7,244,714; of record cited IDS 8/4/23, prior art of record), in view of Strom and Koulmanda (US2017/0190762A1, Application US15/317,136, hereinafter as “Strom”), Glorioso et al (U.S. 2016/0153000 of record cited IDS 8/4/23, prior art of record), Suk et al. (US2013/0323313A1, published 2013, prior art of record), and Coffin et al. (KR100802403, published Feb 13, 2008, prior art of record).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on Dec. 19, 2024, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Regarding claim 45 and 119, Gonda discloses a pharmaceutical composition useful for delivering and expressing one or more polynucleotides encoding an inhaled therapeutic polypeptide to the airways of a subject (see e.g. abstract, col. 19-23, col. 22, lines 56-67, col. 27, lines 12-27, 49-58, col. 28, lines 20-27). Gonda discloses a replication-defective herpes simplex virus (HSV), comprising a recombinant HSV genome (see e.g. col. 22), wherein the recombinant HSV genome comprises the one or more polynucleotide encoding the inhaled therapeutic polypeptide (see e.g. col. 19-22, and esp. col. 22. lns. 31-42). Gonda discloses the use of devices which allows one to control aerodynamic particle size, such as nebulizers (see e.g. col. 15, esp. lines 12-17), with a pharmaceutically acceptable excipient (i.e. buffer)(see e.g. col. 27-28). Further, Gonda discloses wherein the inhaled therapeutic peptide is alpha-1-antityprsin (i.e. AAT)(see e.g. col 20, line 18).
Gonda does not explicitly state wherein the inhaled therapeutic peptide is alpha-1-antityprsin (i.e. AAT) has at least 95% sequence identity to an amino acid sequence SEQ ID NO: 3.
However, the prior art of Strom teaches an Alpha-1 antitrypsin (AAT) amino acid sequence (SEQ ID NO: 10; see .rapbn file; results Dec. 17, 2025, database: Published_Applications_AA_Main), which is an inhaled therapeutic polypeptide having 100% sequence identity to an amino acid sequence SEQ ID NO: 3 (see score alignment below).
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Accordingly, it would have been obvious for one of ordinary skill in the art to prepare the pharmaceutical composition comprising a recombinant HSV as taught by Gonda and incorporate the alpha-1-antityprsin (i.e. AAT) sequence of SEQ ID NO: 3 (i.e. SEQ ID NO: 10) as taught by Strom because both Gonda and Strom disclose utilizing AAT as an inhaled therapeutic polypeptide (Gonda col. 19-22. and Strom para .101). A person of ordinary skill in the art would have a reasonable expectation of success because both disclose using AAT with viral vectors such as a herpes virus (Gonda col. 22 and Strom para. 83). Moreover, a person of ordinary skill in the art would have combined similar gene therapy techniques, which would have led to predictable results with a reasonable expectation of success. Furthermore, an artisan of ordinary skill in the art of (i.e. gene therapy) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Gonda does not explicitly state wherein the herpes simplex virus (HSV) is HSV-1, has reduced toxicity compared to wild-type, where the HSV-1 genome does not comprise a polynucleotide encoding cystic fibrosis transmembrane conductance regulator (CFTR), and a vibrating mesh nebulizer.
However, the prior art of Glorioso discloses non-toxic HSV vectors for pharmaceutical compositions comprising the herpes simplex virus type 1 (HSV-1) that is modified to be non-toxic by inactivating mutations of essential immediate early genes (e.g. ICP22)(see e.g. abstract, paras. 3-8, 16, 104, 60, 71, 98, 106, Figures 1 and 9, claim 5, Example 1). Further, Glorioso discloses wherein the replication-defective HSV-1 (i.e. J∆NI) has reduced cytotoxicity as compared to a corresponding wild-type HSV-1 (i.e. KOS) (see e.g. para. 14-19, Fig. 11-12).
Accordingly, it would have been obvious to a person of ordinary skill in the art to have modified the pharmaceutical composition as taught by Gonda and substituted the HSV of Gonda with the HSV-1 as taught by Glorioso because Glorioso teaches the modified HSV-1 to be non-toxic with the inactivating mutations in essential immediate early genes (e.g. ICP22) (see e.g. paras. 3-8, 16, 104, 60, 98, 106]; Figures 1 and 9, claim 5). Thus, one ordinary skill in the art would have done so because Glorioso teaches an HSV-1 vector that has been modified to reduce its toxicity for gene therapy (see e.g. 0042, 0119). A person of ordinary skill in the art would have a reasonable expectation of success because both Gonda and Glorioso disclose using herpes simplex virus as a vector for efficient gene delivery for therapeutic applications (see e.g. abstracts, respectively). Moreover, a person of ordinary skill in the art would have combined similar gene therapy techniques, which would have led to predictable results with a reasonable expectation of success. Furthermore, an artisan of ordinary skill in the art of (i.e. gene therapy) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Glorioso discloses that that non-toxic HSV-1 vector may encodes one or more prophylactically or therapeutically active proteins in relation to a lung disease. Although Glorioso gives the example of a transmembrane conductance regulator CFTR (see e.g. para. 76).
Nevertheless, the prior art of Strom discloses that Alpha 1-antitrypsin (AAT) compositions and treatments were known for treating a variety of inflammatory diseases including those associated with autoimmunity (e.g. chronic obstructive pulmonary diseases (COPD), diabetes, or graves’ disease)(see e.g. abstract, para. 21, and 114-115) which do not need a transmembrane conductance regulator CFTR.
Accordingly, it would have been obvious for a person of ordinary skill in the art to not have encoded CFTR for any patient with a lung disease, for example a patient with an autoimmune disorder with chronic obstructive pulmonary diseases (COPD). A person of ordinary skill in the art would not have had the recombinant HSV-1 genome encode anything additional to the patient (i.e. anything that the patient did not need for gene therapy). Therefore, it would have been obvious to a person of ordinary skill in the art to have modified the pharmaceutical composition as taught by Gonda and incorporate the HSV-1 as taught by Glorioso with no CFTR as suggested by Strom because Glorioso teaches a modified non-toxic HSV-1 for gene therapy (see e.g. Figures 1 and 9, claim 5). Thus, a person of ordinary skill in the art would have had a reasonable expectation of success. Furthermore, an artisan of ordinary skill in the art of (i.e. gene therapy) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Gonda, Glorioso, and Strom et al., are silent regarding a vibrating mesh nebulizer.
However, the prior art of Suk discloses aerosolized pharmaceutical formulations can be delivered to the lungs, preferably using be a vibrating mesh nebulizer (see e.g. paras. 28, 172, 175, 179).
Accordingly, it would have been obvious to one of ordinary skill in the art to modify the method of Gonda with the vibrating mesh nebulizer as taught by Suk because Suk teaches that the vibrating mesh nebulizer is more effective because it applies a force to which breaks up the liquid formulation into smaller droplets (see e.g. paras. 28, 172, 175, 179). A person of ordinary skill in the art would be motivated to use the electromechanical driving force and improve the nebulizer as taught by Suk in order to generate small droplets as a form a slow moving aerosol stream which can be entrained in an inspiratory flow (see para. 177). Thus, it could have been done with a reasonable expectation of success.
Regarding claims 120, 122-124, as stated supra, Gonda does not explicitly state wherein the herpes simplex virus (HSV) is HSV-1.
However, Glorioso et al, discloses a pharmaceutical wherein the herpes virus is herpes simplex virus type 1 (HSV-1) (e.g. para. 8, 16, 104, Figures 1 and 9).
Regarding claims 120, 122-124, as stated supra, Glorioso teaches the recombinant herpes virus comprising an inactivating deletion in the regulatory region in the essential immediate early gene of ICP22 HSV-1 in order to reduce its toxicity (see e.g. para. 60, 98, and 106). Further, Glorioso teaches the recombinant herpes virus comprising an inactivating deletion in the regulatory region in the essential immediate early gene of ICP22 HSV-1 in order to reduce its toxicity (see e.g. para. 60, 0098, 0106).
Although Gonda teaches HSV and Glorioso teaches that the ICP22 HSV-1 is not to be expressed and teaches deletion of the regulatory region, they do not explicitly state a deletion in the coding region of the ICP22 HSV-1 gene.
However, the prior art of Coffin teaches a recombinant HSV-1 comprising a deletion in the coding region of the ICP22 HSV-1 gene (p. 13, 7th para. of translation).
Accordingly, it would have been obvious to prepare the pharmaceutical composition comprising an inactivated ICP22 HSV-1 gene as taught by Gonda and Glorioso and delete a coding region of the ICP22 HSV-1 gene as taught by Coffin because Coffin teaches that deletion of the coding region of ICP22 HSV-1 gene was a well-known and efficient method for inactivating the gene and would avoid possible expression through cryptic promoters or enhancers. Thus, a person of ordinary skill in the art would have had a reasonable expectation of success. Further, Glorioso discloses that the ICP22 HSV-1 gene should not be expressed, therefore a deletion of the coding gene would have been immediately apparent to one of ordinary skill in virology.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
1.132 Affidavits or declarations traversing rejections or objections.
When any claim of an application or a patent under reexamination is rejected or objected to, any evidence submitted to traverse the rejection or objection on a basis not otherwise provided for must be by way of an oath or declaration under this section. [48 FR 2696, Jan. 20, 1983, effective Feb. 27, 1983; revised, 61 FR 42790, Aug. 19, 1996, effective Sept. 23, 1996; revised, 65 FR 54604, Sept. 8, 2000, effective Sept. 8, 2000; revised 65 FR 57024, Sept. 20, 2000, effective Nov. 29, 2000]
Applicant argues a lack of prima facie case asserting that the combination of cited references fails to teach or suggest a pharmaceutical composition as recited in the pending claims (See Remarks Section A, page 6-7 and 13-14).
Applicants’ arguments with respect to the previous rejection has been fully considered and are persuasive due to the amendments to the claims. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made in view of Gonda et al., Strom and Koulmanda, Glorioso et al, Suk et al. and Coffin et al..
On June 6th, 2025, Applicant filed “Secondary Considerations” (See Remarks, Section B, pages 7-25).
“Rebuttal evidence and arguments can be presented in the specification, In re Soni, 54 F.3d 746, 750, 34 USPQ2d 1684, 1687 (Fed. Cir. 1995), by way of an affidavit or declaration under 37 CFR 1.132, e.g., Soni, 54 F.3d at 750, 34 USPQ2d at 1687; In re Piasecki, 745 F.2d 1468, 1474, 223 USPQ 785, 789-90 (Fed. Cir. 1984), or otherwise presented during prosecution. See, e.g., MPEP §§ 714 to 716 et seq. However, arguments presented by applicant cannot take the place of factually supported objective evidence. See, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984).” (See MPEP 2145)
It is noted that Applicant’s response of secondary considerations has not been submitted in declaration form (see above, 37 CFR 1.132).
The secondary considerations submitted on June 6th, 2025, are acknowledged, considered, and are deemed insufficient to overcome the rejection of instant claims based upon 35 U.S.C 103 as set forth in the last Office action for the following reasons: the secondary considerations assert that the invention works as intended, which includes statements which amount to an affirmation that the claimed subject matter of an HSV-A1AT pharmaceutical composition functions (i.e. HSV-A1AT is well tolerated) as it was intended to function (i.e. no serious adverse events)(fig. 1-4 of Exhibit A)(see Remarks, page 8-9). Furthermore, the issues raised are not relevant to the issue of nonobviousness of the claimed subject matter and provides no objective evidence thereof. See MPEP § 716.
Although evidence of unexpected results must compare the claimed invention with the closest prior art, applicant is not required to compare the claimed invention with subject matter that does not exist in the prior art. In re Geiger, 815 F.2d 686, 689, 2 USPQ2d 1276, 1279 (Fed. Cir. 1987) (Newman, J., concurring) (Evidence rebutted prima facie case by comparing claimed invention with the most relevant prior art. Note that the majority held the Office failed to establish a prima facie case of obviousness.); In re Chapman, 357 F.2d 418, 148 USPQ 711 (CCPA 1966) (Requiring applicant to compare claimed invention with polymer suggested by the combination of references relied upon in the rejection of the claimed invention under 35 U.S.C. 103 "would be requiring comparison of the results of the invention with the results of the invention." 357 F.2d at 422, 148 USPQ at 714.)
Additionally, it is noted that claims are not commensurate in scope with the secondary evidence since the evidence is directed to just Alpha-1-antirypsin and claim 45 recites one or more inhaled therapeutic polypeptides that include other peptides than just Alpha-1-antirypsin, as discussed above (i.e. see 112 rejection).
Applicant argues a successful open-label study, termed SERPENTINE-I; NCT identifier NCT06049082, which is a single dose escalation study in adult patients with apha-1 antitrypsin deficiency (AATD) where the study was designed to include up to three dose escalation cohorts evaluating single administrations of 109, 1010, and 1011 PFU of a replication-defective HSV-1 comprising a recombinant HSV-1 genome encoding an inhaled therapeutic polypeptide (specifically, an alpha-1 antitrypsin (A1AT) polypeptide, termed "HSV-A1AT"). Applicant asserts that they have efficiently produced the encoded human A1AT transgene in a dosage range that is functional and clinically relevant as evidenced by neutrophil elastase inhibition (see Figures 1-4 of Exhibit A, attached herewith)(Remarks, page 8-9).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
Applicants’ response is reminded that in submitting evidence asserted to establish unobvious results, there is a burden on an applicant to indicate how the examples asserted to represent the claimed invention are considered to relate to the examples intended to represent the prior art and, particularly, to indicate how those latter examples do represent the closest prior art. See In re Borkowski, 595 F.2d 713, 184 USPQ 29 (CCPA 1974); In re Goodman, 339 F.2d 228, 144 USPQ 30 (CCPA 1964). It should also be established that the differences in the results are in fact unexpected and unobvious and of both statistical and practical significance. In re Merck, 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986); In re Longi, 759 F. 2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Klosak, 455 F2d 1077, 173 UAPQ 14 (CCPA 1972); In re D’Ancicco, 429 F.2d 1244, 169 USPQ 303 (CCPA 1971 ). Ex parte Gelles, 22 USPQ2d 1318 (BPAI 1992).
In the instant case, it is understood that the open label study was well tolerated and shows an additive effect (i.e. dose escalation study of SERPENTINE and HSV-A1AT)(Exhibit A, fig. 1-3). It is acknowledged that Applicant claims that the composition efficiently produced the encoded human A1AT transgene in a range that is functional and clinically relevant as evidenced by neutrophil elastase inhibition (Fig. 3B). It is acknowledged that the percentage of free neutrophil elastase in ELF is reduced after a single dose of HSV-AIA dose. However, the additive effect of the results does not speak to the composition with the prior art which is required (see MPEP716). Furthermore, these results are not unexpected as Gonda discloses that delivery with DNA formulated with artificial viral envelope (AVE) through a nozzle (i.e. nebulizer) causes increase expression and does not affect cell viability (col. 29-30 of Gonda). Thus, it is also not unexpected that a person of ordinary skill in the art would expect the percentage of free neutrophil elastase in the epithelial lining fluid (ELF) to be reduced upon application of the composition because expression would be increased as taught by Gonda. Furthermore, it is unclear how the secondary considerations are compared to the prior art of Gonda, especially if the composition is working as expected.
Applicant argues that patients not on background IV A1AT augmentation had free A1AT levels in the lung epithelial lining fluid increase over 8-fold after HSV-A1AT dosing (Fig. 3B). Further, Applicant asserts that the unbound neutrophil elastase in epithelial lining fluid dropping from 97.2% at baseline to 40.2%, representing a greater than 50% absolute reduction achieved within 48 hours after dosing (Fig. 3B) (Remarks, page 10).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicants arguments, it appears that the free A1AT levels in the lung epithelial lining fluid (ELF) post dose (Fig. 3B) are significant. It is noted that there is not claim limitation directed to the unbound neutrophil elastase in epithelial lining fluid. As discussed above, it is unclear how the results of free A1AT levels in the lung are compared with the closest prior art (i.e. Gonda) (MPEP 716.02). Therefore, there is not enough data to conclude that the results are unexpected.
Applicant argues that patients on background IV A1AT augmentation are clinically meaningful and support successful gene delivery and expression in the HSV-A1AT treated lung (Fig. 4). Further, Applicant asserts that the levels of A1AT in the serum increased from 4.4 μM to 9.7 μM after HSV-A1AT dosing (Exhibit A)(Remarks, page 11).
Applicant arguments are acknowledged, have been fully considered, and have been deemed partially persuasive.
In response to Applicants arguments, it appears that the level of A1AT in the serum increases after dosage showing successful delivery (Fig. 4) is significant. As discussed above, it is unclear how the results of free A1AT levels in the lung are compared with the closest prior art (i.e. Gonda)(MPEP 716.02). Therefore, there is not enough data to conclude that the results are unexpected.
Applicant asserts that “Applicant has successfully demonstrated the in vivo delivery of a replication-defective herpes simplex virus type 1 comprising a recombinant genome encoding an inhaled therapeutic polypeptide (specifically, an alpha-1 antitrypsin (A1AT) polypeptide, termed "HSV-A1AT") to lung tissue by inhalation using a vibrating mesh nebulizer that provides a consistent dose of HSV-A1AT with limited biodistribution and in the absence of any adverse events (see Figures 5-8 of Exhibit B, attached herewith)(Remarks, page 11-12).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicants argument, it is acknowledged that the Applicant has successfully delivery with limited biodistribution. However, it is unclear how these results are unexpected in view of the prior art. As discussed above, the biodistribution results do not speak to the composition compared with the prior art which is required (see MPEP716). Furthermore, these results are not unexpected as Gonda discloses successful delivery of a formulated composition through a nozzle (i.e. nebulizer) causes increase expression and does not affect cell viability (col. 29-30 of Gonda). Thus, it is unclear how the secondary considerations are compared to the prior art of Gonda, especially if the composition is working as expected.
Applicant argues that the total aerosol concentration and repeatability, determined by both gravimetric (GPA) and chemical (BioSampler) methods (Fig. 6) teaches that the vibrating mesh nebulizer is capable of delivering consistent repeatable doses of HSV-A1AT at the appropriate mass median aerodynamic diameter (MMAD) of 1-5μm to reach human lung tissue upon inhalation (Figure 6C) (Remarks, page 12).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicants argument, it is acknowledged that there is a total aerosol concentration and repeatability by both gravimetric (GPA) and chemical (BioSampler) methods (Fig. 6). It is noted that the results of delivery and repeatability are important to the method claims. However, it is unclear how this asserts unpredictability and is in commensurate in scope with claimed composition. It is acknowledged that HSV-A1AT was measured to have a mass median aerodynamic diameter (MMAD) of 1-5μm to reach human lung tissue upon inhalation (Figure 6C). However, there is not a claim limitation directed to MMAD and it is unclear how this is significant over the prior art of record. As states supra, these results do not appear to be unexpected as Gonda discloses that delivery with DNA formulated with artificial viral envelope (AVE) through a nozzle (i.e. nebulizer) causes increase expression and does not affect cell viability (col. 29-30 of Gonda). The MMAD range results are not being compared with the composition with the closest prior art (see MPEP716).
Applicant argues that HSV-A1AT exposure was highest in the lungs, with little-to-no detection in other tissues, 24 hours (day 23, Figure 5) after the last dose of HSV-A1AT was administered, demonstrating successful delivery to, and retention within, the targeted tissue (lungs) after inhaled delivery to mice (Figure 7)(Remarks, Page 13).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicants argument, it is acknowledged that there is a high level of detection in the lungs regarding the high dosage of HSV-A1AT (Fig. 7). However, it is noted that at low dosage of HSV-A1AT there is detection in the lymph nodes of the males (Fig. 7). It is noted that there is not a claim limitation directed to the dosage of HSV-A1AT and/or time period of the pharmaceutical composition. Thus, the argument is not commensurate in scope with the claims. As discussed above, Applicant has not indicated how this is unexpected over the prior art of Gonda, which discloses aerosolized pharmaceutical formulations can be delivered successfully to the lungs.
Applicant argues that one of ordinary skill in the art would have no reason to expect the superior results presented in Exhibit B in view of the combined teachings of Gonda, Glorioso, and Suk, which yields unexpectedly improved properties sufficient to rebut any prima facie case of obviousness.
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicants arguments, the unexpected evidence is directed to A1AT and are not commensurate in scope with the claims (see list of inhaled therapeutic polypeptides)(see claim 45). As discussed above, Applicants have not shown unexpected results (i.e. delivery of composition) compared to Gonda to rebut any prima facie case of obviousness (see MPEP 716.02). It is acknowledged that Applicants have shown: the composition efficiently produced the encoded human A1AT transgene in a range that is functional and clinically relevant as evidenced by neutrophil elastase inhibition (Fig. 3B), the percentage of free neutrophil elastase in ELF is reduced after a single dose of HSV-AIA dose, and the level of A1AT in the serum increases after the three dosages showing successful delivery (Fig. 4). However, these results do not speak to the composition with the closest prior art (see MPEP716). Thus, it is unclear how the secondary considerations are compared to the prior art of Gonda, especially if the composition is working as expected. In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
No claim is allowed.
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JOSEPHINE GONZALES
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/ Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631