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 .
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 of RCE on November 21, 2025 and amendment after final filed on November 26, 2025 has been entered. Claims 1-90, 96 were canceled, claims 91-5, 108 were amended, claim 117 was newly added and claims 91-95, 97-117 are pending in the instant application.
The restriction was deemed proper and final in the previous office action. Claims 98, 106, 110-114 and 117 are/remain withdrawn from consideration as being drawn to a non-elected species/invention. Claim 117 is withdrawn given it is drawn to a non-elected stabilizing agent species.
Claims 91-95, 97, 99-105 and 107-109, 115-116 are examined on the merits of this office action.
Withdrawn Rejections
The rejection of claims 90-95, 97, 99-104, 108 under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter given that the combination of methionine and rIFNalpha-2b extends the shelf life and thus, is distinct from what occurs in nature.
The rejection of claim(s) 90-94, 99, 103, 108 under 35 U.S.C. 102(a)(1) as being anticipated by Shaabani (Applied Biochem and biotec, pages 1-15, published 2018, cited in Applicant’s IDS dated 7/13/2021) is withdrawn in view of amendment of the claims filed November 26, 2025.
The objection to claim 90 is withdrawn in view of amendment of the claims filed November 26, 2025.
The rejection of claims 90-95, 97, 99-105, 107-109 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of amendment of the claims filed November 26, 2025.
The rejection of Claim(s) 90-94, 99, 100, 103-105, 108 under 35 U.S.C. 103 as being unpatentable over Shaaban (Applied Biochem and biotec, pages 1-15, published 2018, cited previously) in view of in view of Balwani (US20050232899 A1, cited previously) is withdrawn in view of amendment of the claims filed November 26, 2025.
The rejection of Claim(s) 90-94, 99, 100, 103-105, 107-108 under 35 U.S.C. 103 as being unpatentable over Shaaban (Applied Biochem and biotec, pages 1-15, published 2018, cited previously) in view of Cheng (CN105770862A, EPO Translation, cited previously) is withdrawn in view of amendment of the claims filed November 26, 2025.
*Please note that majority of Applicant’s arguments are moot in light of withdrawal of previous rejections. Arguments and responses thereof that remain applicable are found below.
Maintained/Revised Rejections
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.
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.
Claim(s) ) 95, 97, 99, 100-102 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shaaban (Applied Biochem and biotec, pages 1-15, published 2018, cited previously) in view of Grauschopf (US20170360891 A1, cited previously).
Shaaban teaches an Isoform free human interferon alpha-2b at a concentration of 4 mg/mL(see abstract, “Results”, paragraph 1). Shaaban teaches “A rhIFN-α2b isoform has been produced and purified from the refolding reaction using high-resolution anion ion exchange chromatography. This isoform has a proper MW (19 kDa) and high purity and homogeneity”. Shaaban further teaches the purified target peak gave a single sharp symmetrical RP-HPLC peak, not detectable alternative bands on SDS-PAGE and a single intact mass corresponding to 19,337Da thereby evidencing exclusion of other isoforms or impurities and substantially homogenous single isoform preparation (see pages 78-80, Figures 2-5).
Shaaban teaches a formulation with a single rhIFN-a2b isoform with no n-terminal modification and thus, meets the limitations of the instant claims (see figure 3a, 4b). Shaaban teaches “A rhIFN-α2b isoform has been produced and purified from the refolding reaction using high-resolution anion ion exchange chromatography. This isoform has a proper MW (19 kDa) and high purity and homogeneity”. Accordingly, regarding claims 92-93, Shaaban teaches a purified single isoform rhIFN-a2b expressed as a homogenous single isoform protein without N-terminal modification.
Regarding the purity limitations of claim 95 reciting at least 99%, at least 99.5% or 100% purity with respect to degradation isoforms, Shaaban’s disclosure of a single sharp chromatographic peak, absence of heterogeneity, no additional SDS-PAGE bands, and a single intact mass would have conveyed to one of ordinary skill in the art that the preparation was substantially free of alternative isoforms, degradation products, and related impurities. Determining the exact numerical purity level of such highly purified protein preparations would have been a matter of routine optimization (see MPEP 2144.05) using known purification parameters and analytical methods. Further “100 %purity” would be reasonably be understood by one of ordinary skill in the art as no detectable impurity within assay limits rather than absolute theoretical purity
Regarding claim 95, Shaaban teaches injection of a formulation comprising said interferon alpha-2b into an animal and thus would necessarily have an acceptable carrier to be injected (see page 6, “in vivo clearance assay”). In addition, Shaaban teaches sodium phosphate buffer (see page 4, “preparation and purification”). Shaaban teaches high specific activity (see page 9, evaluation of biological (antiviral activity)) and a single isoform N-terminal native like protein (see abstract). Shaaban teaches sodium phosphate buffer (see page 4, “preparation and purification”) which is a stabilizing agent with antioxidant properties.
Regarding claim 99, Shaaban discloses an Isoform free human interferon alpha-2b (single isoform) at a concentration of 4 mg/mL(see abstract, “Results”, paragraph 1).
Shaaban teaches liquid administration via intramuscular injection (see page 6, “in vivo clearance”).
Shaaban is silent to including methionine in the formulation, the specific purity of 99-100% if the isoform free rhIFNa-2b and at a concentration of up to 5 mg/ml.
However, Grauschopf teaches stable alpha type interferon formulations comprising methionine, sodium chloride (see abstract, claim 1) and polysorbate (claims 2-3). Grauschopf teaches replacing benzyl alcohol with L-methionine in combination with polysorbate will result in similar stability. Grauschopf teaches “Since L-Methionine does not form peroxides (in contrast to benzyl alcohol), the formulation according to the present invention can be stored without inert gas (e.g. nitrogen) overlay and hence it has an improved storage stability. Further, the drug product manufacturing process is simplified because L-Methionine (in contrast to benzyl alcohol) is not readily absorbed by or adsorbed to plastics or elastomers which are typically used in the manufacturing process (like e.g. silicone tubing, PTFE tubing, plastic connectors) and it does neither evaporate”. Thus, there are clear advantages to using methionine in combination with polysorbate in place of benzyl alcohol. Grauschopf teaches 5-20 mM L-methionine in the formulation which 10 mM is about 1.5 mg/ml (1.49 mg/mL) meeting the limitations of instant claim 97. Grauschopf therefore teaches methionine functioning as antioxidant stabilizer that minimizes oxidative degradation and improves storage stability of interferon formulations, which would have suggested use of methionine to preserve the folded active conformation of Shaaban’s purified interferon protein during storage.
It would have been obvious at the time of the invention to include methionine/polysorbate in the interferon formulation of Shaaban. One of ordinary skill in the art would have been motivated to do so to improve overall stability and storage stability. There is a reasonable expectation of success given that Grauschopf teaches stable alpha type interferon formulations comprising methionine/polysorbate/NaCl for improving storage stability. It further would have been obvious to optimize the degree of purity and stability of Shaaban’s already highly purified interferon composition through routine purification, formulation and storage condition optimization, yielding purity levels overlapping the claimed ranges and reduced degradation isoforms overtime.
Regarding claim 100, MPEP states “"[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In the instant case, the product of Shaaban and Grauschopf is identical to the instant claims which is a formulation comprising isoform free rhIFN alpha-2b and thus meets the limitations of the claims.
Regarding claims 101-102, Grauschopf teaches stability at temperatures 2-8 degrees Celsius for 24 months falling within the range of instant claims 101-102. To the extent the claims encompass broader temperature ranges, selected workable storage temperatures and durations for a known stable protein formulation would have been routine optimization absent showing of criticality.
As stated above, Regarding the purity limitations of claim 95 reciting at least 99%, at least 99.5% or 100% purity with respect to degradation isoforms, Shaaban’s disclosure of a single sharp chromatographic peak, absence of heterogeneity, no additional SDS-PAGE bands, and a single intact mass would have conveyed to one of ordinary skill in the art that the preparation was substantially free of alternative isoforms, degradation products, and related impurities. Determining the exact numerical purity level of such highly purified protein preparations would have been a matter of routine optimization (see MPEP 2144.05) using known purification parameters and analytical methods. Further “100 %purity” would be reasonably be understood by one of ordinary skill in the art as no detectable impurity within assay limits rather than absolute theoretical purity
Claim(s) ) 109, 115-116 are rejected under 35 U.S.C. 103 as being unpatentable over Shaaban (Applied Biochem and biotec, pages 1-15, published 2018, cited previously) in view of Grauschopf (US20170360891 A1, cited previously) as applied to claims 95, 97, 99-102, in further view of Ruiz (AAPS PharmSciTech 2006; 7 (4) Article 99, cited previously).
The teachings of Shaaban and Grauschopf are provided in the above rejection.
However, the combined references are silent to EDTA and polysorbate 80.
Ruiz teaches that EDTA as a chelating agent with rhIFN-alpha2B reduces aggregation of the protein (see Figure 3) compared to rhIFN-alpha 2b in sodium phosphate buffer alone. Ruiz teaches that “Under these experimental conditions, the role of EDTA might be to capture the trace amounts of metal ions in solution, which otherwise would accelerate several protein degradation reactions, including aggregation. EDTA has been used to stabilize proteins, including rhIFN-α2b, basically because of its ability to inhibit the oxidation reactions by chelating the metal ions in solutions (see E4, left column, paragraphs 2-3). Ruiz further teaches that Polysorbate 20 and 80 (0.5 mg/ml) improved stability of rhIFN-alpha2b and reduced aggregation rate.
It would have been obvious at the time of the invention to include EDTA in the interferon formulations of Shaaban and Grauschopf. One of ordinary skill in the art would have been motivated to do so to stabilize the protein, inhibit aggregation and do so via metal ion chelation. There is a reasonable expectation of success given that Ruiz teaches that EDTA and polysorbate reduced aggregation and improves stability of rhIFN-α2b in a formulation.
Regarding claims 109 and 115, Grauschopf teaches .1-.5 mg/ML alpha type interferon (claim 1) which meets up to 10 mg/mL; 120-150mM NaCL (claim 1, roughly 8.8 mg/mL); 5-20 mM methionine (roughly 20 mM is 2.98 mg/l); pH of 6.5 (see claim 1); Ruiz teaches 0.5 mg/ML of polysorbate 80 and 0.5 mg/mL EDTA. All of these amounts meet the limitations of claim 115 (c) given the generic “up to” language regarding each component.
Furthermore, regarding the amounts of rhIFNalpha-2b, NaCl, EDTA, polysorbate and methionine and the pH (found in instant claims 109, 115-116) it would have been obvious to optimize the amount (within the amounts known of the prior art) of each component given each component is a result effective variable and it would have been obvious to optimize to achieve optimal therapeutic effectiveness and stability (see MPEP 2144.05).
Regarding the limitations of “is stable at freezing, refrigerated and room storage temperatures for a least several months” (Claim 116) or the stability ranging from about -80 to about 40 degrees Celsius for up to six months (claim 109), Shaaban, Grauschopf and Ruiz teaches the same formulation and thus, would inherently have these properties.
Response to Applicant’s Arguments
Applicant argues that “the rejection relies on Ruiz to teach EDTA as a chelating agent as well as polysorbate 20 and 80. The rejection further states it would be obvious to optimize to the claimed amounts of the components within claim 115 per MPEP §2144.05(II)(A) to support a conclusory assertion, such an assertion would be improper per MPEP §2144.05(B) that states only result-effective variables can be optimized. To be a result-effective variable, a particular parameter must first be recognized and only then can that particular parameter be further optimized. Regarding the features of claim 115 Ruiz fails to recognize any result-effective variables associated with the claimed essential oils that may be subsequently optimized. For the above reasons, the Examiner again fails to properly establish prima facie obviousness to claim 115.
Applicant’s arguments have been fully considered but not found persuasive. The rejection does not rely solely on optimization of undisclosed variables. Rather, Ruiz expressly teaches the claimed excipients EDTA and polysorbate 80 in rhIFN-a2b formulations and teaches that such agents reduce aggregation and improve stability. Thus, Ruiz recognizes these formulation components as affecting stability and protein integrity, which are result effective variables. Where the prior art recognizes that a parameter affects a desired property, routine optimization of workable amounts is within the level of ordinary skill in the art.
Further, the rejected claims recite open ended “up to” concentration ranges. Grauschopf teaches interferon concentrations overlapping the claimed ranges, Ruiz teaches 0.5 mg/ml EDTA and polysorbate 80, and Grauschopf teaches methionine and NaCL amounts falling within or reasonably close to the recited limits. Selecting or adjusting amounts within these known workable ranges to obtain a stable interferon formulation would have been obvious through routine experimentation.
Applicants argument that Ruiz must expressly identify each claimed concentration as a result effective variable is misplaced. A reference need not disclose the exact claimed values where it teaches the same components for the same purpose and would have suggested optimization of their amounts to a person of ordinary skill in the art. Accordingly, the rejection is maintained.
New Objections
Claims 91 and 92 ultimately depend on a claim that is not a preceding claim. A series of singular dependent claims is permissible in which a dependent claim refers to a preceding claim which, in turn, refers to another preceding claim. A claim which depends from a dependent claim should not be separated by any claim which does not also depend from said dependent claim. It should be kept in mind that a dependent claim may refer to any preceding independent claim. In general, applicant's sequence will not be changed. See MPEP § 608.01 (n).
Claim 93 is objected to for the following informality: the limitation of “stabilizing agent” in lines 5 and 7 should be replaced with “water soluble stabilizing agent” to be consistent throughout the claim.
Claim 95 is objected to for the following informality: the limitation of “stabilizing agent” in lines 10 and 12 should be replaced with “water soluble stabilizing agent” to be consistent throughout the claim.
New Rejections
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 92, 99, 101, 103, 116 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 92 claims “a homogenous single isoform N-terminal”. This phrase is unclear because it does not distinctly identify the structural characteristic being claimed. It is uncertain whether the limitation requires a homogenous population of molecules having the same N-terminal sequence, a single isoform defined by N-terminal identity, absence of N-terminal variants or modifications or a combination thereof. Applicants specification provides no guidance with respect to what is meant by “a homogenous single isoform N-terminal”. Applicant should clarify this point of confusion.
Claim 99 claims “The formulation of claim 95, wherein the single isoform rhIFN a-2b is provided in a desired concentration per ml or in an amount of up to 10 mg/ml; up to 15 mg/ml; about 10 pg/ml to about 400 pg/ml; or about 5.0 MIU/ml.” The term desired concentration is a subjective term and fails to provide an objective boundary for the claimed concentration, such that one of ordinary skill in the art would not be able to determine the scope of the claim.
Claim 101 recites that the formulation is stable at temperatures ranging from about -80 degrees C to about 40 degrees C for up to 1 month, up to 2 months, up to 3 months, up to 6 months, up to 1 year and up to 2 years. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 101 recites the broad recitation up to 2 years but then also recite that the stability is up to 1 month which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 103 claims “The formulation of claim 95, formulated as a liquid for administration via inhalation, intravenous, intramuscular, intrathecal, parenteral or intravaginal, and wherein the liquid is a liquid aerosol, liquid droplets, liquid mist or as a liquid spray.” It is unclear whether the recited forms of the liquid (liquid aerosol, liquid droplets, liquid mist, or liquid spray) apply to each of the listed administration routes, or only to certain routes such as inhalation or intravaginal administration. For example, aerosol, mist, spray, and droplets are ordinarily associated with inhalation or topical delivery, whereas intravenous, intramuscular, and intrathecal administration ordinarily involve injectable sterile liquid preparations. Thus, the claim sets forth inconsistent or ambiguous relationships between the dosage form and the recited routes of administration.
Accordingly, one of ordinary skill in the art would not be able to determine with reasonable certainty the metes and bounds of claim 103.
Claims 101 and 116 recite that the formulation is “stable” under recited storage conditions. However, “stable” is a term of degree and neither the claims nor the specification provide an objective standard for measuring stability, such a retention of potency, purity, activity, concentrations, aggregation or degradation threshold. Accordingly, one of ordinary skill in the art would not be reasonably able to determine the metes and bounds of the claimed subject matter.
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.
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.
Claim(s) ) 103-105, 108 are rejected under 35 U.S.C. 103 as being unpatentable over Shaaban (Applied Biochem and biotec, pages 1-15, published 2018, cited previously) in view of Grauschopf (US20170360891 A1, cited previously) as applied to claims 95, 97, 99-102, in further view of Balwani (US20050232899 A1, cited previously) and Puri (J Clin Exp Hepatol 2012 Nov 1;2(4):396–398).
The teachings of Shaaban in view of Grauschopf are provided in the above rejection. The teachings of Shaaban in view of Grauschopf are directed to rhIFNa-2b formulations for use in treating viral infections such as HCV.
Shaaban in view of Grauschopf is silent to use of the formulation via inhalation (or in an inhaler (aerosol or spray) in powder or liquid form) (relevant to instant claims 103-105).
However, Balwani teaches use of and delivery of alpha-type interferon formulations via aerosol delivery of the liquid (see abstract, claim 79). Balwani teaches “Although the present inventors are not certain of the reasons behind the increased pharmacodynamic responses of the aerosolized deliveries relative to subcutaneous injection, these characteristics can provide certain advantages over subcutaneous delivery of alpha-interferon. For example, a much smaller dose can be given by aerosol to a patient on a daily basis, with expectation of achieving the same pharmacodynamic response as if a much larger dose was given subcutaneously or intravenously every three days, which is currently the practice” (See paragraph 0080). Balwani teaches use in a nebulizer (see paragraph 0066). Balwani additionally teaches other anti-viral agents can be used (see paragraph 0062) and monoclonal antibodies (see paragraph 0063).
It would have been obvious at the time of the invention to aerosolize the purified single isoform interferon formulations Shaaban in view of Grauschopf as taught by Balawani for delivery to the lungs for treatment of lung viral infections. One of ordinary skill in the art would have been motivated to do so to allow for smaller doses that are effective on a daily bases as oppose to larger disease and with the formulations of Shaaban in view of Grauschopf that have antiviral activity with high purity and less immunogenicity . There is a reasonable expectation of success given that Balwani teaches successful aerosolization and therapeutic delivery of alpha-type interferon formulations via the lungs which maintain the activity (antiviral) and the stability of the protein at lower doses.
Regarding claim 108, Puri teaches “25(OH)D3 is a novel anti-HCV agent that targets an infectious viral particle assembly step. This finding provides insight into the improved efficacy of anti-HCV treatment via the combination of vitamin D3 and IFN. Our results also suggest that 25(OH)D3, not vitamin D3, is a better therapeutic option in patients with hepatic dysfunction and reduced enzymatic activity for generation of 25(OH)D3” (see Conclusion of Abstract 1).
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known
herbicides held prima facie obvious). But see In re Geiger, 815 F.2d 686, 2 USPQ2d 1276 (Fed. Cir. 1987) (“Based upon the prior art and the fact that each of the three components of the composition used in the claimed method is conventionally employed in the art for treating cooling water systems, the board held that it would have been prima facie obvious, within the meaning of 35 U.S.C. 103, to employ these components in combination for their known functions and to optimize the amount of each additive....Appellant argues... hindsight reconstruction or at best,... obvious to try’.... We agree with appellant.”). One of ordinary skilled in the art would have been motivated to combine the two each known (rhIFNa-2b and vitamin D) to be useful for the same purpose (inhibiting HCV infections), with a reasonable expectation that at least here will be an additive effect.
Claim(s) ) 107 is rejected under 35 U.S.C. 103 as being unpatentable over Shaaban (Applied Biochem and biotec, pages 1-15, published 2018, cited previously) in view of Grauschopf (US20170360891 A1, cited previously) as applied to claims 95, 97, 99-102, in further view of Jiang (CN1672731 A, EPO Translation, cited previously).
The teachings of Shaaban in view of Grauschopf are provided in the above rejection. The teachings of Shaaban in view of Grauschopf are directed to rhIFNa-2b formulations for use in treating viral infections such as HCV. Shaaban in view of Grauschopf teaches purified homogeneous single isoform human recombinant interferon a-2b without an N-terminal modification, methionine, a purity of 99% or more. Shaaban in view of Grauschopf is silent to use of the formulation via inhalation (or in an inhaler in powder or liquid form) and lyophilization.
However, Jiang teaches dry powder inhaler formulations comprising interferon (see abstract, paragraph 0002). Jiang teaches that there are shortcomings to injecting interferon α-2b for hepatitis because of higher risk of infection, adaptability and expense (see paragraph 0005). Jiang teaches wherein the powder for inhalation to the lung is human interferon α-2b (see paragraph 0023). Jiang teaches the powder should have a particle size of 2-4 microns (See paragraph 0039). Jiang teaches spray dry or lyophilization to remove all water and produce a dry powder (see paragraph 0031, translation). Jiang teaches advantages include less enzymes for degradation in the lung, suitable for long term, drug absorption is fast and less toxic effects (see paragraph 0006).
It would have been obvious at the time of the invention to aerosolize the purified single isoform interferon formulations of Shaaban (as a dry powder inhalant) for effective delivery for treatment of viral infection. One of ordinary skill in the art would have been motivated to do so because Jiang teaches pulmonary delivery of interferon alpha 2b avoids disadvantages associated with injectable hIFNa2b administration, including risk of infection, inconvenience, and higher cost, while providing rapid absorption, targeted delivery to the lungs, reduced toxicity and suitability for long term administration. There would have been a reasonable expectation of successful formulation and delivery of alpha type interferon as a dry powder inhalant that maintains antiviral activity and therapeutic efficacy upon pulmonary administration.
Regarding claim 107, Jiang teaches metered dosage inhalers by teaching dry powder inhalers with set dosing amounts (see paragraph 0046).
Claim(s) ) 91-94 are rejected under 35 U.S.C. 103 as being unpatentable over Shaaban (Applied Biochem and biotec, pages 1-15, published 2018, cited previously) in view of Grauschopf (US20170360891 A1, cited previously) and Jiang (CN1672731 A, EPO Translation, cited previously).
Shaaban teaches an Isoform free human interferon alpha-2b at a concentration of 4 mg/mL(see abstract, “Results”, paragraph 1). Shaaban teaches “A rhIFN-α2b isoform has been produced and purified from the refolding reaction using high-resolution anion ion exchange chromatography. This isoform has a proper MW (19 kDa) and high purity and homogeneity”. Shaaban further teaches the purified target peak gave a single sharp symmetrical RP-HPLC peak, not detectable alternative bands on SDS-PAGE and a single intact mass corresponding to 19,337Da thereby evidencing exclusion of other isoforms or impurities and substantially homogenous single isoform preparation (see pages 78-80, Figures 2-5).
Shaaban teaches a formulation with a single rhIFN-a2b isoform with no n-terminal modification and thus, meets the limitations of the instant claims (see figure 3a, 4b). Shaaban teaches “A rhIFN-α2b isoform has been produced and purified from the refolding reaction using high-resolution anion ion exchange chromatography. This isoform has a proper MW (19 kDa) and high purity and homogeneity”. Accordingly, regarding claims 92-93, Shaaban teaches a purified single isoform rhIFN-a2b expressed as a homogenous single isoform protein without N-terminal modification.
Regarding the purity limitations of claim 91 reciting at least 99%, at least 99.5% or 100% purity with respect to degradation isoforms, Shaaban’s disclosure of a single sharp chromatographic peak, absence of heterogeneity, no additional SDS-PAGE bands, and a single intact mass would have conveyed to one of ordinary skill in the art that the preparation was substantially free of alternative isoforms, degradation products, and related impurities. Determining the exact numerical purity level of such highly purified protein preparations would have been a matter of routine optimization (see MPEP 2144.05) using known purification parameters and analytical methods. Further “100 %purity” would be reasonably be understood by one of ordinary skill in the art as no detectable impurity within assay limits rather than absolute theoretical purity
Regarding claim 94, Shaaban teaches injection of a formulation comprising said interferon alpha-2b into an animal and thus would necessarily have an acceptable carrier to be injected (see page 6, “in vivo clearance assay”). In addition, Shaaban teaches sodium phosphate buffer (see page 4, “preparation and purification”). Shaaban teaches high specific activity (see page 9, evaluation of biological (antiviral activity)) and a single isoform N-terminal native like protein (see abstract). Shaaban teaches sodium phosphate buffer (see page 4, “preparation and purification”) which is a stabilizing agent with antioxidant properties.
Shaaban is silent to including methionine in the formulation, the specific purity of 99-100% if the isoform free rhIFNa-2b and lyophilization.
However, Grauschopf teaches stable alpha type interferon formulations comprising methionine, sodium chloride (see abstract, claim 1) and polysorbate (claims 2-3). Grauschopf teaches replacing benzyl alcohol with L-methionine in combination with polysorbate will result in similar stability. Grauschopf teaches “Since L-Methionine does not form peroxides (in contrast to benzyl alcohol), the formulation according to the present invention can be stored without inert gas (e.g. nitrogen) overlay and hence it has an improved storage stability. Further, the drug product manufacturing process is simplified because L-Methionine (in contrast to benzyl alcohol) is not readily absorbed by or adsorbed to plastics or elastomers which are typically used in the manufacturing process (like e.g. silicone tubing, PTFE tubing, plastic connectors) and it does neither evaporate”. Thus, there are clear advantages to using methionine in combination with polysorbate in place of benzyl alcohol. Grauschopf teaches 5-20 mM L-methionine in the formulation which 10 mM is about 1.5 mg/ml (1.49 mg/mL) meeting the limitations of instant claim 97. Grauschopf therefore teaches methionine functioning as antioxidant stabilizer that minimizes oxidative degradation and improves storage stability of interferon formulations, which would have suggested use of methionine to preserve the folded active conformation of Shaaban’s purified interferon protein during storage.
It would have been obvious at the time of the invention to include methionine/polysorbate in the interferon formulation of Shaaban. One of ordinary skill in the art would have been motivated to do so to improve overall stability and storage stability. There is a reasonable expectation of success given that Grauschopf teaches stable alpha type interferon formulations comprising methionine/polysorbate/NaCl for improving storage stability. It further would have been obvious to optimize the degree of purity and stability of Shaaban’s already highly purified interferon composition through routine purification, formulation and storage condition optimization, yielding purity levels overlapping the claimed ranges and reduced degradation isoforms overtime.
As stated above, Regarding the purity limitations of claim 91 reciting at least 99%, at least 99.5% or 100% purity with respect to degradation isoforms, Shaaban’s disclosure of a single sharp chromatographic peak, absence of heterogeneity, no additional SDS-PAGE bands, and a single intact mass would have conveyed to one of ordinary skill in the art that the preparation was substantially free of alternative isoforms, degradation products, and related impurities. Determining the exact numerical purity level of such highly purified protein preparations would have been a matter of routine optimization (see MPEP 2144.05) using known purification parameters and analytical methods. Further “100 %purity” would be reasonably be understood by one of ordinary skill in the art as no detectable impurity within assay limits rather than absolute theoretical purity
As stated above, Shaaban in view of Grauschopf is silent to use of the formulation via inhalation (or in an inhaler in powder or liquid form) and lyophilization.
However, Jiang teaches dry powder inhaler formulations comprising interferon (see abstract, paragraph 0002). Jiang teaches that there are shortcomings to injecting interferon α-2b for hepatitis because of higher risk of infection, adaptability and expense (see paragraph 0005). Jiang teaches wherein the powder for inhalation to the lung is human interferon α-2b (see paragraph 0023). Jiang teaches the powder should have a particle size of 2-4 microns (See paragraph 0039). Jiang teaches spray dry or lyophilization to remove all water and produce a dry powder (see paragraph 0031, translation). Jiang teaches advantages include less enzymes for degradation in the lung, suitable for long term, drug absorption is fast and less toxic effects (see paragraph 0006).
It would have been obvious at the time of the invention to aerosolize the purified single isoform interferon formulations of Shaaban (as a dry powder inhalant) for effective delivery for treatment of viral infection. One of ordinary skill in the art would have been motivated to do so because Jiang teaches pulmonary delivery of interferon alpha 2b avoids disadvantages associated with injectable hIFNa2b administration, including risk of infection, inconvenience, and higher cost, while providing rapid absorption, targeted delivery to the lungs, reduced toxicity and suitability for long term administration. There would have been a reasonable expectation of successful formulation and delivery of alpha type interferon as a dry powder inhalant that maintains antiviral activity and therapeutic efficacy upon pulmonary administration.
Regarding claim 92, Shaaban in view of Grauschopf teach the identical lyophilized composition of the instant claims and thus, would inherently have the property of antiviral activity sufficient to protect 50% of cells against viral damage (see MPEP 2112).
Conclusion
No claims are allowed.
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/ERINNE R DABKOWSKI/ Examiner, Art Unit 1654
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