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 .
Claim Rejections 35 USC 102(A)(1)
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.
Claim(s) 1, 3-5, 7, 8 and 11-16 are rejected under 35 U.S.C. 102(A)(1) as being anticipated by Martini et al. (Cell Dev. Biol., 22 October 2020, Vol. 8, p. 1-5).
Martini teaches that the Alpha-1 antitrypsin (AAT) protein is one of the major serum proteins involved in anti-inflammatory processes, and that it is mainly synthesized in the liver and released into the bloodstream (p. 1, para. 3). This reference further teaches that AAT is primarily known as a serine protease inhibitor (SERPIN), targeting several enzymes involved in tissue damage/repair, and its activity is very high in the lower respiratory tract where it provides over 90% of the defenses against proteases, (mainly neutrophil elastase) to protect healthy tissues from the digestive action of proteolytic enzymes (p. 1). This reference further teaches that, as an acute phase protein, AAT increases 4-6 fold during infections, inflammation, tissue injury, surgery and late pregnancy (p. 1, para. 3). Martini further teaches that AAT therapy is the only available pharmacological treatment that can slow COPD progression in AAT deficient patients (p. 2, Col. 1, para. 3) This reference teaches that COPD is a respiratory disease characterized by persistent respiratory symptoms with significant obstruction of airflow, and increased lung and systemic inflammation (p. 2, Col. 1). Martini also teaches that COPD progression is associated with increased inflammation of the airway and alveolar COPD patients frequently present exacerbations, often triggered by bacterial/viral respiratory infections or viruses, which lead to disease progression through an exaggerated inflammatory response (p. 2, Col. 1). Martini also teaches that AAT supplement therapy is largely used to avoid disease exacerbation in AAT deficient COPD patients and that COVID19 and COPD patients present similar clinical outcomes, such as acute exacerbations, resulting in exaggerated inflammatory response and increased NRL and IL6 levels (p. 2, Col. 2, para. 3).
Regarding treating and preventing Covid and other viral infections, Martini teaches that COPD is associated with a 5.9-fold higher risk of progression in patients with COVID-19 and that AAT is a potential COVID19 treatment because it acts as an efficient inhibitor of the host transmembrane protease serine 2 (TMPRSS2) protein receptor, which is essential during the initial phase of the SARS-CoV2 infection (p. 3, Col. 1, para. 1). Additionally, this reference teaches that AAT augmentation may be useful to modulate the production and activity of key pro-inflammatory cytokines, while preserving the production of the anti-inflammatory cytokine IL-10, and it can be used to prevent severe outcomes in COVID-19 patients (p. 3, para. 1). This reference further teaches that AAT administration is an FDA-approved as an aerosol formulation for inhalation, with a confirmed safety profile, and that it has therapeutic potential to treat and counteract COVID-19 (p. 3, Col. 1, para. 2). Finally, this reference teaches that AAT treatment via aerosol could be administered in COVID-19 patients as a local instillation or aerosol in humid heat vaporization (40– 41◦C) in the first phase of COVID-19 as a powerful therapeutic to treat and reduce the progression of SARS-CoV-2 entering into the host cells, by inhibiting host cell receptors, which would significantly reduce viral replication and evolution into more severe clinical outcomes (p. 3, Col. 2, para. 3).
This meets the limitations of claims 1 and 12-15 by teaching that COPD patients are FDA approved for aerosol AAT administration, which meets the limitation of “reducing the risk of a viral infection,” as the human patient class is any subject for which this likelihood could be reduced. Furthermore, Martini teaches that COPD patients are more at risk than the general population for COVID-19 infection. Claim 3-5 and 16 are met because an aerosol is a form of solid drug particles suspended in gas, which includes a spray and powder.. Claims 7 and 8 are met because Martini teaches aerosol administration, which necessarily requires a device to administer the particles suspended in gas. As to claim 11, the specification does not provide any guidelines as to how one would measure being “suspected of having a viral infection.” As such, Martini’s teaching that COPD patients have a 5.9 fold higher risk for COVID-19 satisfies this limitation.
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.
Claim(s) 1-9 and 11-18 are rejected under 35 U.S.C. 103 as being unpatentable over Martini et al. (Cell Dev. Biol., 22 October 2020, Vol. 8, p. 1-5) in view of Hubbard et al. (Expert Opin. Biol. Ther. (2012) 12(6) 687).
The teachings of Martini have been described supra.
The difference between the prior art and the instant claims is that the prior art does not teach the concentration of AAT in solution.
Hubbard et al teach that AAT reconstituted with sterile water, is a solution containing active AAT at a concentration of 25 mg/ml (p. 569, para. 2). This reference further teaches that AAT may be used as a nebulizer, with aerosol droplets for inhalation (Fig. 3). This reference teaches that studies in sheep further demonstrated that the aerosolized pAAT and rAAT were each able to pass through alveolar epithelium and gain access to the interstitial compartment of the lung, thus increasing anti-elastase defenses of the lung intersitium (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention, to have taken the method of preventing viral infections and used a nebulizer as the route of administering AAT because Hubbard teaches that this is a viable route for administering AAT solution via inhalation. One would be motivated to do so because Hubbard teaches that aerosolized AAT was able to pass through alveolar epithelium into the interstitial compartment of the lung. As such, there is a reasonable expectation of success that the nebulizer formulation of Hubbard can be effectively used in the in vivo viral prevention method taught by Martini.
Therefore, the solution and nebulizer limitations of claims 2 and 6 are met, as nebulizers require a solution for inhalation.
As to the concentrations of claims 9, 17 and 18, the MPEP states: 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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was "unexpectedly good"); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
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As such, it would have been obvious to optimize the concentration of AAT in the inhaled formulation of Martini and Hubbard.
Claim(s) 1, 3-5, 7, 8 and 10-16 are rejected under 35 U.S.C. 103 as being unpatentable over Martini et al. (Cell Dev. Biol., 22 October 2020, Vol. 8, p. 1-5) in view of Monahan et al. (US20030087250A1).
The teachings of Martini have been described supra.
The difference between the prior art and the instant claims is that the prior art does not teach that the sequence of AAT is SEQ ID NO: 3.
However, Monahan teaches human AAT, SEQ ID NO 286, which is 100% identical to instantly claimed SEQ ID NO 3:
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It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to have taken the method of Martini and used the human AAT of Monahan. One would be motivated to do so because Monahan teaches treatments and prevention methods for humans, and human AAT would be the logical choice for the AAT sequence, as it is the same species. As such, there is a reasonable expectation of success that the peptide of Monahan can be effectively used with in the human treatments taught by Monahan.
As such, claim 10 is rendered obvious.
Non-Statutory 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 1-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/723,224 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘224 teach the following:
1. A method for treating a viral respiratory infection, comprising administering a recombinant alpha1-antitrysin (AAT) protein or a fragment thereof expressed in a genetically modified yeast to a subject in need thereof.
2. The method according to claim 1, wherein the viral respiratory infection is a SARS Coronavirus infection.
3. The method according to claim 2, wherein the viral respiratory infection is SARS-CoV-2.
4. The method according to claim 1, wherein the viral respiratory infection is an influenza virus infection or respiratory syncytial virus (RSV).
5. The method according to claim 1, wherein the AAT protein or fragment thereof comprises a sequence according to SEQ ID NO 3 or 5 or is encoded by SEQ ID NO 1, 2 or 4.
6. The method according to claim 1, wherein the recombinant AAT protein or fragment thereof has a serum half-life and/or activity not less than AAT purified from human plasma.
7. The method according to claim 1, wherein the recombinant AAT protein or fragment thereof is expressed in a yeast of the family Saccharomycesaceae.
8. The method according to claim 1, wherein the recombinant AAT protein or fragment thereof is expressed in Pichia pastoris.
9. The method according to claim 1, wherein the recombinant AAT protein or fragment thereof comprises post-translational modifications.
10. The method according to claim 9, wherein the post-translation modification is one or more of O-glycosylation, N-glycosylation, N-terminal methionine removal, N-acetylation and/or phosphorylation or any combination thereof.
11. The method according to claim 1, wherein the AAT protein or fragment thereof is administered by inhalation.
12. The method according to claim 1, wherein the AAT protein or fragment thereof is administered by inhalation of a nebulized solution.
13. The method according to claim 1, wherein the viral infection is SARS-CoV-2, the AAT protein or fragment thereof is expressed from Pichia pastoris, and the AAT protein or fragment thereof is administered by inhalation of a nebulized solution.
14. The method according to claim 1, wherein the viral infection is an Influenza virus, and the AAT protein or fragment thereof is expressed from Pichia pastoris, and the AAT protein or fragment thereof is administered by inhalation of a nebulized solution.
15. The method according to claim 1, wherein the viral infection is SARS-CoV-2, and the AAT protein or fragment thereof is expressed from Pichia pastoris and isolated using chromatography, and the AAT protein or fragment thereof is administered by inhalation of a nebulized solution.
16. The method according to claim 1, wherein the AAT protein or fragment thereof is produced from genetically modified yeast, in a method comprising the steps of: a. culturing a genetically modified yeast comprising an exogenous nucleic acid molecule with an AAT-encoding region operably linked to a promoter or promoter/enhancer combination, wherein said yeast is Pichia pastoris, b. expressing recombinant AAT or fragment thereof in the cultured yeast, wherein the promoter is glyceraldehyde-3-phosphate dehydrogenase (GAP) or alcohol oxidase I (AOX1), and c. isolating recombinant AAT or fragment thereof from the culture.
17. The method according to claim 1, wherein the AAT protein or fragment is secreted from the yeast into a culture medium, to a concentration of at least 1 mg protein per litre of liquid medium (mg/L).
18. The method according to claim 1, comprising administering a pharmaceutical composition, said composition comprising the recombinant AAT protein or fragment thereof and a pharmaceutically acceptable carrier.
19. The method according to claim 18, wherein the composition is a solution administered by inhalation, a soluble powder administered by inhalation or a dry powder administered by inhalation.
20. The method according to claim 1, wherein the viral respiratory infection is a respiratory syncytial virus (RSV) infection.
Instant claims 1, 2 and 6 are met because claim 1 of ‘224 teaches treating viral infection with AAT and claims 11, 12 and 14 teach inhalation using a nebulizer. Instant claims 3, 4, 7 and 16 are met because claim 19 teaches an inhalable dry powder, which comprises small particles. Claims 5 and 8 are met because inhalation must be done via nasal, oral or respiratory tract administration. Claims 11-15 are met because claims 2 and 3 of ‘224 teach treating SARS-CoV-2. Claims 10 is met because claim 5 teaches SEQ ID NOs: 1-3.
As to claims 9, 17 and 18, these concentrations would have been obvious to optimize by routine experimentation, as discussed above in reference to MPEP 2144.05.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEANETTE M LIEB whose telephone number is (571)270-3490. The examiner can normally be reached M-F 10-7.
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/JEANETTE M LIEB/Primary Examiner, Art Unit 1654