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 .
Election/Restrictions
Applicant’s election without traverse of Group I (i.e., claims 1-3, 5-6, 8-9, 11-13, 15, 17-19, 21-22, 25-26, 28, and 30 directed to an aqueous solution) in the reply filed on April 30, 2024, is acknowledged. Additionally, Applicant’s election without traverse of Species A (i.e., a single and specific aqueous solution composition as including terlipressin acetate at a concentration of 0.01-5 mg/ml, acetate buffer at a concentration of 0.1-5 mM, proline at a concentration of 1-100 mM, and mannitol as an uncharged tonicity modifier at a concentration of 50-1000 mM where the composition does not contain a charged tonicity modifier and non-ionic surfactant) in the reply filed on April 30, 2024, is acknowledged. It is further noted that since not expressly indicated that the composition contains a preservative, the Examiner is interpreting Applicant’s election such that the composition does not contain a preservative.
Please note that the amino acid component of Species A is expanded to include aspartic acid, glycine, methionine, arginine, glutamic acid, histidine, and lysine; and the tonicity modifier component of Species A is expanded to include glycerol, sorbitol, sucrose, trehalose and lactose in light of the Examiner’s search results.
Also please note that claims 35-37 are hereby rejoined and examined given that Applicants have amended the claims such that the elected concentration of an uncharged tonicity modifier is no longer recited. Thus, examination is extended to the next species, i.e., 200-500 mM and about 300 mM.
Status of Claims
Claims 1-32 were originally filed on June 21, 2021.
The amendment received on June 21, 2021, canceled claims 4, 7, 10, 14, 16, 20, 23-24, 27, 29, and 31; and amended claims 1-3, 5-6, 8-9, 11-13, 15, 17-19, 21-22, 25-26, 28, 30, and 32. The amendment received on November 26, 2024, canceled claim 8; amended claims 1-3, 9, 11-12, 15, and 17-18; and added new claims 33-37. The amendment received on April 9, 2025, amended claims 1, 3, 11-13, 17-18, and 35-37. The amendment received on April 16, 2026, canceled claim 32; and added new claims 38-39.
Claims 1-3, 5-6, 9, 11-13, 15, 17-19, 21-22, 25-26, 28, 30, and 33-39 are currently pending and claims 1-3, 6, 9, 11-13, 15, 17-18, 28, 30, and 33-39 are under consideration as claims 5, 19-22, and 25-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on April 30, 2024.
Priority
The present application claims status as a 371 (National Stage) of PCT/GB2019/053645 filed December 20, 2019, and claims priority under 119(a)-(d) to British Application Nos. 1909264.2 filed on June 27, 2019, and 1821148.2 filed on December 21, 2018.
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d) for British Application Nos. 1909264.2 and 1821148.2, which papers have been placed of record in the file. Please note that the British applications are in English and therefore no further action is necessary.
New Rejections Necessitated by Amendment
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 1-3, 6, 9, 11-13, 15, 28, 30, 33, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Malm WO 2019/239386 A1 published on December 19, 2019 (effective filing date of June 15, 2018) (cited in the IDS received on 6/21/21), in view of Warne et al. US 2008/0064856 A1 published on March 13, 2008, alone or as evidenced by DrugBank Online, “Terlipressin”, DrugBank Online, available online at https://go.drugbank.com/drugs/DB02638, 11 pages (first available 2005), Product Information, GLYPRESSIN® Solution for Injection, available online at www.tga.gov.au/sites/default/files/auspar-terlipressin-acetate-121126-pi.pdf, 18 pages (2012) (hereinafter “the Glypressin reference”) (cited in the Action mailed on 12/19/24), Chawathe et al., Anal. Bioanal Chem. 417:4311-4329 (2025), Hunt, “Chapter 27: Amino Acids, Peptides and Proteins,” available online at www.chem.ucalgary.ca/courses/351/Carey5th/Ch27/ch27-1-4-2.html, 1 page (accessed on 7/17/24) (cited in the Action mailed on 7/26/24), and Important Biological Buffers, available online at http://staff.ustc.edu.cn/~liuyz/methods/buffer.htm, 2 pages (accessed on 12/13/24) (hereinafter “the buffer reference”) (cited in the Action mailed on 12/19/24).
For claims 1-3, 6, 12, 15, 28, 30, and 38-39, with respect to an aqueous solution composition having a pH in the range of 4.0-6.0 comprising 0.01-50 mg/ml terlipressin or a salt thereof, and one or more buffers having at least one ionizable group with a pKa in the range of 3.0 to 7.0 and which pKa is within 1 pH unit of the pH of the composition and wherein the one or more buffers are present in the composition at a total concentration of 0-5 mM as recited in instant claim 1; with respect to where the concentration of terlipressin or salt thereof is 0.01-1 mg/ml as recited in instant claim 2; with respect to where the total concentration of the one or more buffers in the composition is 0.1-5 mM as recited in instant claim 3; with respect to where the one or more buffers is benzoate or acetate as recited in instant claim 6; with respect to where the terlipressin is employed as terlipressin acetate as recited in instant claim 28; with respect to an aqueous solution composition of claim 1 which is a pharmaceutical composition as recited in instant claim 30; and with respect to where the composition comprises acetate as recited in instant claims 38-39:
Malm teaches in Table 1 a formulation containing 0.1 mg/ml of terlipressin and acetate as a buffer salt at a concentration of 5 mM where the formulation has a pH of 4.5 (See Malm specification, [0101]; Table 1). Moreover, Malm teaches in Table 4, a terlipressin acetate formulation comprising 0.1 mg/ml of terlipressin acetate, and 1 mM sodium acetate where the formulation has a pH of 4.6 and where the terlipressin acetate contributes about 0.2 mM which is included in the sodium acetate concentration thereby corresponding to a total acetate concentration of 1.2 mM (See Malm specification, [0116]; Table 4 (Formulation 7A)). Alternatively, Malm teaches that the buffer salt can be present in an amount to provide a total buffer concentration ranging from about 0.1 mM to about 5 mM, and the pH of the terlipressin compositions can range from about 4.5 to about 6 (See Malm specification, [0006], [0008], [0040]). Plus, regarding that the formulation/composition is in the form of a solution, Malm teaches that terlipressin is known to be available as a solution for injection (i.e., GLYPRESSIN), but Malm sought to develop a liquid terlipressin formulation with improved shelf-life that is stable at room temperature for at least 1-2 years (See Malm specification, [0005]). As evidenced by the Glypressin reference, the active ingredient is terlipressin, but the drug substance included in this product contains non-stoichiometric amounts of acetic acid and water (See Glypressin reference, pg. 1, 3rd paragraph). Water is also listed as an excipient for GLYPRESSIN (See Glypressin reference, pg. 1, 7th paragraph). As such, the formulations taught by Malm would be in an aqueous solution form. Thus, the teachings of Malm expressly teach a specific embodiment that satisfies the claim limitations with respect to an aqueous pharmaceutical composition in the form of a solution having a pH in the range of 4.0-6.0 comprising 0.01-50 mg/ml terlipressin or terlipressin in the form of terlipressin acetate and acetate as a buffer that is present in a total concentration of 0-5 mM as recited in instant claims 1, 6, 12, 15, 28, 30, and 38-39, with respect to where the concentration of terlipressin is 0.01-1 mg/ml or 0.1-1 mg/ml as recited in instant claim 2, with respect to where the total concentration of the one or more buffers in the composition is 0.1-5 mM or 0.5-5 mM as recited in instant claims 3 and 15.
For claims 1, 9, 11-13, and 33, with respect where the aqueous solution further comprises an amino acid where the amino acid is present at a concentration of 1-5 mM as recited in instant claims 1 and 12; with respect to where the amino acid is glycine, proline, methionine, arginine, lysine, aspartic acid, glutamic acid, and histidine as recited in instant claims 9, 13, and 33; and with respect to where the amino acid is present at a concentration of 1-4, 1-3, or 1-2 mM as recited in instant claims 11 and 13:
Malm teaches that terlipressin is also known as triglycyl-lysine vasopressin, and is an analogue of vasopressin (See Malm specification, [0004]). As evidenced by DrugBank, compared to endogenous vasopressin, terlipressin has a longer half-life and increased selectivity for the V1 receptor (See DrugBank, pg. 1, background section). As such, terlipressin exhibits improved properties compared to vasopressin. Moreover, as discussed supra for claim 1, Malm sought to develop a liquid terlipressin formulation with improved shelf-life that is stable at room temperature for at least 1-2 years (See Malm specification, [0005]). Thus, Malm sought terlipressin formulations that exhibited improved stability enabling for an improved shelf-life at room temperature. However, Malm does not expressly teach or suggest that the pharmaceutical composition further comprises an amino acid at a concentration of 1-5 mM.
Warne et al. teaches protein formulations exhibiting reduced aggregation properties by adding methionine to the formulation at a concentration of about 0.5 mM to about 145 mM where the protein does not contain a methionine residue and the aggregation is not due to methionine oxidation thereby increasing shelf-life and maintaining the biological activity of the formulation (See Warne, [0006]-[0007], [0015]-[0016], [0039]). Warne et al. also teaches that methionine is added to the formulation to a final concentration of between about 0.5 mM to about 50 mM (See Warne, [0008], [0015], [0019]), and claims a concentration range of about 1 mM to 25 mM (See Warne, claim 17). The proteins that benefit from the addition of methionine are those known to aggregate or considered likely to aggregate including antibodies, coagulation factors, ligands, enzymes, etc.; for example, a protein within a formulation aggregates during storage, as a result of elevated temperature, or exposure to light (See Warne, [0010], [0019], [0055]). Although Warne does not expressly identify terlipressin as a protein that would benefit from the addition of methionine, the commercially available terlipressin formulation is known to be stored in a refrigerator at 2°C to 8°C in a carton to protect from light as evidenced by the Glypressin reference, (See Glypressin reference, pg. 8, 6th paragraph). Furthermore, as evidenced by Chawathe et al., using high-resolution mass spectrometry, the researchers found that terlipressin degrades into 11 different degradation products resulting from several modifications (See Chawathe, abstract; Figure 16). Thus, terlipressin is susceptible to storage degradation and likely degradation due to light exposure.
Warne et al. defines “aggregate” as a physical interaction between protein molecules that results in the formation of covalent or non-covalent dimers or oligomers, which may remain soluble or form insoluble aggregates that precipitate out of solution (See Warne, [0040]). Warne et al. teaches that one major problem with protein formulations is that they can lose their biological activity as a result of the formation of soluble or insoluble aggregates (See Warne, [0038]). Aggregation is a degraded protein state, and therefore, minimizing it results in increased shelf life, potency or activity of a protein formulation (See Warne, [0038]). There are many factors that affect protein aggregation including storage, exposure to elevated temperatures, exposure to shear stress, and exposure to light (See Warne, [0041]-[0043]). Warne et al. notes that the addition of methionine reduces aggregation regardless of what causes a protein to aggregate (See Warne, [0047]). Additional amino acids that reduce protein aggregation include arginine, lysine, glycine glutamic acid, or aspartic acid and are present in a concentration ranging from 0.5 mM to 50 mM (See Warne, [0050]-[0051]). Therefore, the teachings of Warne et al. suggest adding methionine in a concentration ranging from about 0.5 mM to about 50 mM or about 1 mM to 25 mM to protein formulations where the protein does not contain a methionine residue in order to reduce aggregation properties not due to methionine oxidation thereby increasing shelf-life and maintaining the biological activity of the formulation.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to modify the teachings of Malm and add an amino acid such as methionine as a stabilizer at a concentration of about 1 to 25 mM to an aqueous pharmaceutical composition comprising terlipressin acetate at a concentration of 0.1 mg/ml, acetate at a concentration of 1 mM or 5 mM as a buffer in order to stabilize the terlipressin in the composition by reducing aggregation properties, improving the composition’s shell-life for storage at room temperature, and maintaining the biological activity of the formulation. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because adding methionine at a concentration of about 0.5 to about 50 mM or of about 1 mM to 25 mM to a protein formulation where the protein does not contain a methionine residue was known to reduce aggregation properties not due to methionine oxidation thereby increasing shelf-life and maintaining the biological activity of the formulation as taught by Warne et al. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the pharmaceutical composition of Malm comprises terlipressin, which is known to be stored in a refrigerator at 2°C to 8°C in a carton to protect from light and result in 11 degradation products, and acetate as a buffer at a concentration of about 0.1 to about 5 mM at a pH of 4.5 to 6. Therefore, adding methionine as a stabilizer in a concentration of about 1 mM to 25 mM would support the stabilization of the terlipressin in the composition by reducing aggregation properties, improving the composition’s shell-life for storage at room temperature, and maintaining the biological activity of the formulation by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant KSR.
Regarding the methionine concentration being 1 mM to 5 mM, MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%". The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.) Moreover, the Federal Circuit found that a prima facie case existed where a claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms and the prior art taught that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." In re Geisler, 116 F.3d 1465, 1469-82, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997). Therefore, the claimed concentration of methionine would have been obvious to one of ordinary skill in the art since the prior art concentration range (i.e., 0.5 mM to 50 mM or about 1 mM to 25 mM) overlaps with the claimed concentration range (i.e., 1-5 mM).
For claims 1 and 12, with respect to where the amino acid which does not comprise an ionizable group with a pKa within 1 pH unit of the pH of the composition:
Malm does not expressly teach an amino acid which does not comprise an ionizable group with a pKa within 1 pH unit of the pH of the composition. Although Malm teaches specific embodiments where the pH of the composition is 4.5 or 4.6 as discussed supra, Malm also broadly teaches that the pH of the terlipressin compositions can range from about 4.5 to about 6 (See Malm, [0006]).
As discussed for claims 1, 9, 12-13, and 33, the teachings of Warne et al. suggest adding methionine to protein formulations in order to stabilize the protein in the formulation. It is noted that Malm teaches that the pH of the composition ranges from about 4.5 to about 6. As evidenced by Hunt, methionine (i.e., pKa1 = 2.28 and pKa2 = 9.21) as taught by Warne et al. does not comprise an ionizable group with a pKa within 1 pH unit of the pH of the composition. Thus, Warne et al. suggest adding an amino acid as a stabilizer to a protein formulation where the amino acid does not comprise an ionizable group with a pKa within 1 pH unit of the pH of the composition as recited in instant claims 1 and 12.
For claims 1 and 15, with respect to where the one or more buffers having at least one ionizable group with a pKa in the range 3.0 to 7.0 and which pKa is within 1 pH unit of the pH of the composition:
Malm does not expressly teach one or more buffers having at least one ionizable group with a pKa in the range 3.0 to 7.0 and which pKa is within 1 pH unit of the pH of the composition.
As discussed supra for claims 1, 3, 6, and 15, the teachings of Malm suggest utilizing acetate as a buffer in the terlipressin formulation. It is noted that Malm teaches that the pH of the composition is 4.5 and 4.6. As evidenced by the buffer reference, acetate has a pKa at 25°C of 4.76 (See buffer reference, pg. 1, col. 1). Thus, Malm suggests adding a buffer to the terlipressin formulation where the buffer having at least one ionizable group with a pKa in the range 3.0 to 7.0 and is within 1 pH unit of the pH of the composition, i.e., 4.5 or 4.6 as recited in instant claims 1 and 15.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Maintained/Modified Rejections in light of Applicants’ Amendments
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 1-3, 6, 9, 11-13, 15, 17-18, 28, 30, and 33-37 are rejected under 35 U.S.C. 103 as being unpatentable over Malm WO 2019/239386 A1 published on December 19, 2019 (effective filing date of June 15, 2018) (cited in the IDS received on 6/21/21), in view of Kocherlakota et al. US 2021/0093553 A1 published on April 1, 2021 (effective filing date of 12/22/17), Warne et al. US 2008/0064856 A1 published on March 13, 2008, alone or as evidenced by DrugBank Online, “Terlipressin”, DrugBank Online, available online at https://go.drugbank.com/drugs/DB02638, 11 pages (first available 2005), Product Information, GLYPRESSIN® Solution for Injection, available online at www.tga.gov.au/sites/default/files/auspar-terlipressin-acetate-121126-pi.pdf, 18 pages (2012) (hereinafter “the Glypressin reference”) (cited in the Action mailed on 12/19/24), Chawathe et al., Anal. Bioanal Chem. 417:4311-4329 (2025), Hunt, “Chapter 27: Amino Acids, Peptides and Proteins,” available online at www.chem.ucalgary.ca/courses/351/Carey5th/Ch27/ch27-1-4-2.html, 1 page (accessed on 7/17/24) (cited in the Action mailed on 7/26/24), and Important Biological Buffers, available online at http://staff.ustc.edu.cn/~liuyz/methods/buffer.htm, 2 pages (accessed on 12/13/24) (hereinafter “the buffer reference”) (cited in the Action mailed on 12/19/24).
For claims 1-3, 6, 12, 15, 28, and 30, with respect to an aqueous solution composition having a pH in the range of 4.0-6.0 comprising 0.01-50 mg/ml terlipressin or a salt thereof, and one or more buffers having at least one ionizable group with a pKa in the range of 3.0 to 7.0 and which pKa is within 1 pH unit of the pH of the composition and wherein the one or more buffers are present in the composition at a total concentration of 0-5 mM as recited in instant claim 1; with respect to where the concentration of terlipressin or salt thereof is 0.01-1 mg/ml as recited in instant claim 2; with respect to where the total concentration of the one or more buffers in the composition is 0.1-5 mM as recited in instant claim 3; with respect to where the one or more buffers is benzoate or acetate as recited in instant claim 6; with respect to where the terlipressin is employed as terlipressin acetate as recited in instant claim 28; with respect to an aqueous solution composition of claim 1 which is a pharmaceutical composition as recited in instant claim 30:
Malm teaches in Table 1 a formulation containing 0.1 mg/ml of terlipressin and acetate as a buffer salt at a concentration of 5 mM where the formulation has a pH of 4.5 (See Malm specification, [0101]; Table 1). Moreover, Malm teaches in Table 4, a terlipressin acetate formulation comprising 0.1 mg/ml of terlipressin acetate, and 1 mM sodium acetate where the formulation has a pH of 4.6 and where the terlipressin acetate contributes about 0.2 mM which is included in the sodium acetate concentration thereby corresponding to a total acetate concentration of 1.2 mM (See Malm specification, [0116]; Table 4 (Formulation 7A)). Alternatively, Malm teaches that the buffer salt can be benzoate that is present in an amount to provide a total buffer concentration ranging from about 0.1 mM to about 5 mM, and the pH of the terlipressin compositions can range from about 4.5 to about 6 (See Malm specification, [0006], [0008], [0040]). Plus, regarding that the formulation/composition is in the form of a solution, Malm teaches that terlipressin is known to be available as a solution for injection (i.e., GLYPRESSIN), but Malm sought to develop a liquid terlipressin formulation with improved shelf-life that is stable at room temperature for at least 1-2 years (See Malm specification, [0005]). As evidenced by the Glypressin reference, the active ingredient is terlipressin, but the drug substance included in this product contains non-stoichiometric amounts of acetic acid and water (See Glypressin reference, pg. 1, 3rd paragraph). Water is also listed as an excipient for GLYPRESSIN (See Glypressin reference, pg. 1, 7th paragraph). As such, the formulations taught by Malm would be in an aqueous solution form. Thus, the teachings of Malm expressly teach a specific embodiment that satisfies the claim limitations with respect to an aqueous pharmaceutical composition in the form of a solution having a pH in the range of 4.0-6.0 comprising 0.01-50 mg/ml terlipressin or terlipressin in the form of terlipressin acetate and acetate or benzoate as a buffer that is present in a total concentration of 0-5 mM as recited in instant claims 1, 6, 12, 15, 28, and 30, with respect to where the concentration of terlipressin is 0.01-1 mg/ml or 0.1-1 mg/ml as recited in instant claim 2, with respect to where the total concentration of the one or more buffers in the composition is 0.1-5 mM or 0.5-5 mM as recited in instant claims 3 and 15.
For claims 1, 9, and 11-13, with respect where the aqueous solution further comprises an amino acid where the amino acid is present at a concentration of 1-5 mM as recited in instant claims 1 and 12; with respect to where the amino acid is glycine, proline, methionine, arginine, lysine, aspartic acid, glutamic acid, and histidine as recited in instant claim 9; and with respect to where the amino acid is present at a concentration of 1-4, 1-3, or 1-2 mM as recited in instant claims 11 and 13:
Malm teaches that terlipressin is also known as triglycyl-lysine vasopressin, and is an analogue of vasopressin (See Malm specification, [0004]). As evidenced by DrugBank, compared to endogenous vasopressin, terlipressin has a longer half-life and increased selectivity for the V1 receptor (See DrugBank, pg. 1, background section). As such, terlipressin exhibits improved properties compared to vasopressin. Moreover, as discussed supra for claim 1, Malm sought to develop a liquid terlipressin formulation with improved shelf-life that is stable at room temperature for at least 1-2 years (See Malm specification, [0005]). Thus, Malm sought terlipressin formulations that exhibited improved stability enabling for an improved shelf-life at room temperature. However, Malm does not expressly teach or suggest that the pharmaceutical composition further comprises an amino acid.
Kocherlakota et al. teaches stable parenteral formulations of vasopressin comprising one or more stabilizers and is free of acetate (See Kocherlakota, [0011]-[0012]). In particular, Kocherlakota et al. teaches stable parenteral formulations of vasopressin comprising stabilizers and other pharmaceutically acceptable excipients where the stabilizer comprises (i) one or more buffers and (ii) optionally one or more excipients selected from amino acids and chelating agents (See Kocherlakota, [0013], [0025]). “Stable” is defined as meaning that the formulations remain stable during the entire shelf-life of the composition such that the formulation shows an assay of 90-110% of the original assay value when stored under specified controlled conditions (See Kocherlakota, [0017]). Kocherlakota et al. teaches that the vasopressin formulations were found to be stable over wide range of pH, the conventional vasopressin formulations had a pH ranging from 2.5-4.5 (See Kocherlakota, [0022], [0024]). Moreover, Kocherlakota et al. teaches that stabilizers play a significant role in maintaining the stability of vasopressin in liquid formulations (See Kocherlakota, [0025]). Amino acids that function as stabilizers include arginine, glycine, alanine, proline, methionine, lysine, leucine, cysteine and isoleucine (See Kocherlakota, [0025]). When present, an amino acid is present in an amount of 0 to 10% w/v (See Kocherlakota, [0043]) thereby equating to a concentration of 0 mM to 670 mM for methionine (i.e., molar mass is 149.21 g/mol), 0 mM to 1332 mM for glycine (i.e., molar mass is 75.07 g/mol), and 0 mM to 868 mM for proline (i.e., molar mass is 115.13 g/mol). Buffers include benzoate, and water is the most common solvent (See Kocherlakota, [0025]-[0026]). Kocherlakota et al. also teaches that the pharmaceutical compositions can contain other pharmaceutically acceptable excipients such as antioxidants, preservatives, tonicity modifiers and pH adjusting excipients (See Kocherlakota, [0027]). Specific vasopressin formulation contained 0.26 mg/ml aspartic acid and 0.9 mg isoleucine (See Kocherlakota, [0051], [0058]) thereby equating to a concentration of 1.95 mM for aspartic acid (i.e., molar mass is 133.1 g/mol) and 6.8 mM for isoleucine (i.e., molar mass is 131.18 g/mol). Thus, Kocherlakota et al. suggests adding amino acids as stabilizers to vasopressin liquid formulations such as arginine, glycine, alanine, proline, methionine, lysine, leucine, cysteine and isoleucine with a specific embodiment of about 1.95 mM aspartic acid where such inclusion of an amino acid stabilizer improved the formulation’s shelf-life stability.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to modify the teachings of Malm and add an amino acid such as aspartic acid as a stabilizer at a concentration of about 1.95 mM to an aqueous pharmaceutical composition comprising terlipressin acetate at a concentration of 0.1 mg/ml, acetate or benzoate at a concentration of 1 mM or 5 mM as a buffer in order to stabilize the terlipressin in the composition and improve the composition’s shell-life for storage at room temperature. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because a vasopressin composition was known to exhibit improved shelf-life stability when stabilizers such as aspartic acid at a concentration of about 1.95 mM and benzoate as a buffer are added as taught by Kocherlakota et al. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the pharmaceutical composition of Malm comprises terlipressin as a known vasopressin analogue exhibiting improved half-life and increased selectivity for the V1 receptor, and acetate or benzoate as a buffer at a concentration of about 0.1 to about 5 mM at a pH of 4.5 to 6. Therefore, adding aspartic acid as a stabilizer in a concentration of about 1.95 mM would support the improved shelf-life stability of the pharmaceutical composition when stored at room temperature by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant KSR.
For claims 1 and 12, with respect to where the amino acid which does not comprise an ionizable group with a pKa within 1 pH unit of the pH of the composition:
Malm does not expressly teach an amino acid which does not comprise an ionizable group with a pKa within 1 pH unit of the pH of the composition. Although Malm teaches specific embodiments where the pH of the composition is 4.5 or 4.6 as discussed supra, Malm also broadly teaches that the pH of the terlipressin compositions can range from about 4.5 to about 6 (See Malm, [0006]).
As discussed for claims 1, 9, 12-13, and 33, the teachings of Kocherlakota et al. suggest adding aspartic acid to vasopressin formulations in order to stabilize the protein in the formulation. It is noted that Malm teaches that the pH of the composition ranges from about 4.5 to about 6. As evidenced by Hunt, methionine and proline taught by Kocherlakota et al. as protein stabilizers do not comprise an ionizable group with a pKa within 1 pH unit of the pH of the composition. Although Hunt evidences that one of the pKa’s of aspartic acid has a value that could fall within 1 pH unit of the pH of the composition, an ordinary skilled artisan would routinely optimize the pH such that it is above 4.65 (See Hunt reference, Table). Thus, Kocherlakota et al. suggest adding an amino acid as a stabilizer to a protein formulation where the amino acid does not comprise an ionizable group with a pKa within 1 pH unit of the pH of the composition as recited in instant claims 1 and 12.
For claims 1 and 15, with respect to where the one or more buffers having at least one ionizable group with a pKa in the range 3.0 to 7.0 and which pKa is within 1 pH unit of the pH of the composition:
Malm does not expressly teach one or more buffers having at least one ionizable group with a pKa in the range 3.0 to 7.0 and which pKa is within 1 pH unit of the pH of the composition.
As discussed supra for claims 1, 3, 6, and 15, the teachings of Malm suggest utilizing acetate as a buffer in the terlipressin formulation. It is noted that Malm teaches that the pH of the composition is 4.5 and 4.6. As evidenced by the buffer reference, acetate has a pKa at 25°C of 4.76 (See buffer reference, pg. 1, col. 1). Thus, Malm suggests adding a buffer to the terlipressin formulation where the buffer having at least one ionizable group with a pKa in the range 3.0 to 7.0 and is within 1 pH unit of the pH of the composition, i.e., 4.5 or 4.6 as recited in instant claims 1 and 15.
For claims 9, 11, 13, and 33, with respect to where the amino acid is glycine, proline, methionine, arginine, lysine, aspartic acid, glutamic acid, and histidine as recited in instant claim 9; with respect to where the amino acid is present at a concentration of 1-4, 1-3, or 1-2 mM as recited in instant claims 11 and 13; and with respect to where the amino acid is methionine, glycine or proline as recited in instant claims 13 and 33:
As stated supra for claims 1, 9, and 11-13, Malm does not expressly teach or suggest that the pharmaceutical composition further comprises an amino acid. Kocherlakota et al. suggests adding amino acids as stabilizers to vasopressin liquid formulations such as arginine, glycine, alanine, proline, methionine, lysine, leucine, cysteine and isoleucine with a specific embodiment of about 1.95 mM aspartic acid where such inclusion of an amino acid stabilizer improved the formulation’s shelf-life stability. Kocherlakota also teaches that when present, an amino acid is present in an amount of 0 to 10% w/v (See Kocherlakota, [0043]) thereby equating to a concentration of 0 mM to 670 mM for methionine (i.e., molar mass is 149.21 g/mol), 0 mM to 1332 mM for glycine (i.e., molar mass is 75.07 g/mol), and 0 mM to 868 mM for proline (i.e., molar mass is 115.13 g/mol).
Warne et al. teaches protein formulations exhibiting reduced aggregation properties by adding methionine to the formulation at a concentration of about 0.5 mM to about 145 mM where the protein does not contain a methionine residue and the aggregation is not due to methionine oxidation thereby increasing shelf-life and maintaining the biological activity of the formulation (See Warne, [0006]-[0007], [0015]-[0016], [0039]). Warne et al. also teaches that methionine is added to the formulation to a final concentration of between about 0.5 mM to about 50 mM (See Warne, [0008], [0015], [0019]). The proteins that benefit from the addition of methionine are those known to aggregate or considered likely to aggregate including antibodies, coagulation factors, ligands, enzymes, etc.; for example, a protein within a formulation aggregates during storage, as a result of elevated temperature, or exposure to light (See Warne, [0010], [0019], [0055]). Although Warne does not expressly identify terlipressin as a protein that would benefit from the addition of methionine, the commercially available terlipressin formulation is known to be stored in a refrigerator at 2°C to 8°C in a carton to protect from light as evidenced by the Glypressin reference, (See Glypressin reference, pg. 8, 6th paragraph). Furthermore, as evidenced by Chawathe et al., using high-resolution mass spectrometry, the researchers found that terlipressin degrades into 11 different degradation products resulting from several modifications (See Chawathe, abstract; Figure 16). Thus, terlipressin is susceptible to storage degradation and likely degradation due to light exposure.
Warne et al. defines “aggregate” as a physical interaction between protein molecules that results in the formation of covalent or non-covalent dimers or oligomers, which may remain soluble or form insoluble aggregates that precipitate out of solution (See Warne, [0040]). Warne et al. teaches that one major problem with protein formulations is that they can lose their biological activity as a result of the formation of soluble or insoluble aggregates (See Warne, [0038]). Aggregation is a degraded protein state, and therefore, minimizing it results in increased shelf life, potency or activity of a protein formulation (See Warne, [0038]). There are many factors that affect protein aggregation including storage, exposure to elevated temperatures, exposure to shear stress, and exposure to light (See Warne, [0041]-[0043]). Warne et al. notes that the addition of methionine reduces aggregation regardless of what causes a protein to aggregate (See Warne, [0047]). Additional amino acids that reduce protein aggregation include arginine, lysine, glycine glutamic acid, or aspartic acid and are present in a concentration ranging from 0.5 mM to 50 mM (See Warne, [0050]-[0051]). Therefore, the teachings of Warne et al. suggest adding methionine in a concentration ranging from about 0.5 mM to about 50 mM to protein formulations where the protein does not contain a methionine residue in order to reduce aggregation properties not due to methionine oxidation thereby increasing shelf-life and maintaining the biological activity of the formulation.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to modify the teachings of Malm and add an amino acid such as methionine as a stabilizer at a concentration of about 0.5 to about 50 mM or proline at concentration ranging above 0 to 868 mM to an aqueous pharmaceutical composition comprising terlipressin acetate at a concentration of 0.1 mg/ml, acetate or benzoate at a concentration of 1 mM or 5 mM as a buffer in order to stabilize the terlipressin in the composition by reducing aggregation properties, improving the composition’s shell-life for storage at room temperature, and maintaining the biological activity of the formulation. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because a vasopressin composition was known to exhibit improved shelf-life stability when stabilizers such as methionine at a concentration of above 0 mM to 670 mM or proline at a concentration ranging above 0 to 868 mM, and benzoate as a buffer are added as taught by Kocherlakota et al.; and because adding methionine at a concentration of about 0.5 to about 50 mM to a protein formulation where the protein does not contain a methionine residue was known to reduce aggregation properties not due to methionine oxidation thereby increasing shelf-life and maintaining the biological activity of the formulation as taught by Warne et al. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the pharmaceutical composition of Malm comprises terlipressin, which is known to be stored in a refrigerator at 2°C to 8°C in a carton to protect from light and result in 11 degradation products, and acetate or benzoate as a buffer at a concentration of about 0.1 to about 5 mM at a pH of 4.5 to 6. Therefore, adding methionine as a stabilizer in a concentration of about 0.5 mM to 50 mM or proline as a stabilizer in a concentration of above 0 to 868 mM would support the stabilization of the terlipressin in the composition by reducing aggregation properties, improving the composition’s shell-life for storage at room temperature, and maintaining the biological activity of the formulation by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant KSR.
Regarding the methionine or proline concentration being 1 mM to 5 mM, MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%". The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.) Moreover, the Federal Circuit found that a prima facie case existed where a claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms and the prior art taught that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." In re Geisler, 116 F.3d 1465, 1469-82, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997). Therefore, the claimed concentration of methionine would have been obvious to one of ordinary skill in the art since the prior art concentration range (i.e., 0.5 mM to 50 mM) overlaps with the claimed concentration range (i.e., 1-5 mM), and the claimed concentration of methionine would have been obvious to one of ordinary skill in the art since the prior art concentration range (i.e., above 0 mM to 868 mM) overlaps with the claimed concentration range (i.e., 1-5 mM).
For claims 17-18 and 35-36, with respect to where the composition further comprises an uncharged tonicity modifier such as lactose in an amount of 200-500 mM or about 300 mM:
Although Malm teaches including mannitol as an isotonic agent (Malm claim 3), Malm’s provisional supporting application does not support mannitol as an isotonic agent. As such, relying on Malm’s effective filing date, Malm does not expressly teach including mannitol as an uncharged tonicity modifier.
Kocherlakota et al. teaches that stabilizers other excipients such as lactose, solvents such as PEG, antioxidants, preservatives, tonicity modifiers, and pH adjusting excipients (See Kocherlakota, [0025]-[0027]). In Example 6, the vasopressin formulation contains 5-15 mg/ml lactose (See Kocherlakota, [0069]) thereby equating to a concentration ranging from 146 mM to 438 mM (i.e., molar mass of lactose is 342.3 g/mol, and thus, 5/342.3 x 1000 = 146 mM and 15/342.3 x 1000 = 438 mM). Thus, Kocherlakota et al. suggests adding lactose as a stabilizer to vasopressin liquid formulations with specific embodiments of 146 mM to 438 mM where such inclusion of lactose as a stabilizer improved the formulation’s shelf-life stability.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to modify the teachings of Malm and add aspartic acid at a concentration of about 1.95 mM and lactose at a concentration of 146 mM to 438 mM as stabilizers to an aqueous pharmaceutical composition comprising terlipressin acetate at a concentration of 0.1 mg/ml, and acetate or benzoate at a concentration of 1 mM or 5 mM as a buffer in order to stabilize the terlipressin in the composition and improve the composition’s shell-life for storage at room temperature. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because a vasopressin composition was known to exhibit improved shelf-life stability when stabilizers such as aspartic acid at a concentration of about 1.95 mM, lactose at a concentration of 146 mM to 438 mM, and benzoate as a buffer are added as taught by Kocherlakota et al. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the pharmaceutical composition of Malm comprises terlipressin as a known vasopressin analogue exhibiting improved half-life and increased selectivity for the V1 receptor, and acetate or benzoate as a buffer at a concentration of about 0.1 to about 5 mM at a pH of 4.5 to 6. Therefore, adding aspartic acid and lactose as stabilizers in a concentration of about 1.95 mM and a range of 146 mM to 438 mM, respectively, would support the improved shelf-life stability of the pharmaceutical composition when stored at room temperature by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant KSR.
Regarding the uncharged tonicity modifier concentration being 200 mM to 500 mM, MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%". The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.) Moreover, the Federal Circuit found that a prima facie case existed where a claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms and the prior art taught that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." In re Geisler, 116 F.3d 1465, 1469-82, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997). Therefore, the claimed concentration of the uncharged tonicity modifier (i.e., lactose) would have been obvious to one of ordinary skill in the art since the prior art concentration range (i.e., 146 mM to 438 mM) overlaps with the claimed concentration range (i.e., 200-500 mM or about 300 mM).
For claims 34 and 37, with respect to where the tonicity modifier is mannitol or sorbitol:
As discussed supra, Kocherlakota et al. teaches that stabilizers other excipients such as lactose, solvents such as PEG, antioxidants, preservatives, tonicity modifiers, and pH adjusting excipients (See Kocherlakota, [0025]-[0027]).
Warne et al. also teaches that the protein formulations can contain other substances such as cryoprotectants, lyoprotectants, surfactants, bulking agents, antioxidants, and stabilizing agents (See Warne, [0070]). Mannitol and lactose can both be used as bulking agents that provide structure of freeze-dried product without interacting directly with the pharmaceutical product, provide freeze-thaw protection, and enhance the protein stability over long-term storage (See Warne, [0074). Warne et al. also teaches that mannitol can be added to the protein formulation as a free radical scavenger in an amount from about 0.01% to about 25% (See Warne, [0051]). Thus, the teachings of Warne et al. demonstrate that an ordinary skilled artisan can substitute lactose with mannitol.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to modify the teachings of Malm and add aspartic acid at a concentration of about 1.95 mM and mannitol instead of lactose at a concentration of 274 mM to 823 mM (i.e., molar mass of mannitol is 182.172 g/mol thereby equating to 5/182.172 x1000 = 274 mM and 15/182.172 x 1000 = 823 mM) as stabilizers to an aqueous pharmaceutical composition comprising terlipressin acetate at a concentration of 0.1 mg/ml, and acetate or benzoate at a concentration of 1 mM or 5 mM as a buffer in order to stabilize the terlipressin in the composition and improve the composition’s shell-life for storage at room temperature. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because a vasopressin composition was known to exhibit improved shelf-life stability when stabilizers such as aspartic acid at a concentration of about 1.95 mM, lactose at a concentration of 146 mM to 438 mM, and benzoate as a buffer are added as taught by Kocherlakota et al.; and because adding mannitol and lactose were known to be added as stabilizers to a protein formulation where the protein does not contain a methionine residue in order to reduce aggregation properties by increasing shelf-life and maintaining the biological activity of the formulation as taught by Warne et al. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the pharmaceutical composition of Malm comprises terlipressin as a known vasopressin analogue exhibiting improved half-life and increased selectivity for the V1 receptor, and acetate or benzoate as a buffer at a concentration of about 0.1 to about 5 mM at a pH of 4.5 to 6. Therefore, adding aspartic acid and mannitol instead of lactose as stabilizers in a concentration of about 1.95 mM and a range of 274 mM to 823 mM, respectively, would support the improved shelf-life stability of the pharmaceutical composition when stored at room temperature by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant KSR.
Regarding the uncharged tonicity modifier concentration being 200 mM to 500 mM or about 300 mM, MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%". The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.) Moreover, the Federal Circuit found that a prima facie case existed where a claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms and the prior art taught that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." In re Geisler, 116 F.3d 1465, 1469-82, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997). Therefore, the claimed concentration of the uncharged tonicity modifier (i.e., mannitol) would have been obvious to one of ordinary skill in the art since the prior art concentration range (i.e., 274 mM to 823 mM) overlaps with the claimed concentration range (i.e., 200-500 mM or about 300 mM).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 4/16/26 for claims 1-3, 6, 9, 11-13, 15, 17-18, 28, 30, and 33-37 have been fully considered but they are not persuasive for the following reasons.
In response to Applicant’s first argument, i.e., Malm describes acetate-based terlipressin stabilization that relies on acetate as the buffer, and thus, an ordinary skilled artisan would lack a reasonable expectation of success in departing from Malm’s highly optimized and verified acetate system (See Applicant’s Response received on 4/16/26, pg. 7), it is found unpersuasive. Pursuant to MPEP 2121(III) states that a prior art reference provides an enabling disclosure and thus anticipates a claimed invention if the reference describes the claimed invention in sufficient detail to enable a person of ordinary skill in the art to carry out the claimed invention; "proof of efficacy is not required for a prior art reference to be enabling for purposes of anticipation." Impax Labs. Inc. v. Aventis Pharm. Inc., 468 F.3d 1366, 1383, 81 USPQ2d 1001, 1013 (Fed. Cir. 2006). MPEP 716.07 states that since in a patent it is presumed that a process if used by one skilled in the art will produce the product or result described therein, such presumption is not overcome by a mere showing that it is possible to operate within the disclosure without obtaining the alleged product. In re Weber, 405 F.2d 1403, 160 USPQ 549 (CCPA 1969). Moreover, pursuant to MPEP 2152.02(b), in order for a prior art document to describe a claimed invention under AIA 35 U.S.C. 102(a)(1) or (a)(2), the prior art document need only describe and enable one skilled in the art to make a single species or embodiment of the claimed invention. See Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1562, 19 USPQ2d 1111, 1115 (Fed. Cir. 1991). In the instant case, it is acknowledged that Malm utilized acetate as the buffer in the terlipressin formulations in the Examples finding that acetate improved terlipressin storage degradation. However, it is noted that Malm specifically identifies acetate or benzoate as the buffer that would result in the improved terlipressin storage degradation. Malm’s Example 1 demonstrates that citrate and succinate react with terlipressin thereby leading to high impurity levels (See Malm, [0102]). As such, Malm excludes citrate or succinate as the buffer. But Malm expressly suggests that the buffer be a monovalent organic buffer identifying two specific species of buffers that would improve terlipressin storage degradation; namely, acetate and benzoate. Notably, citrate and succinate are not monovalent buffers, and thus, not suggested by Malm to be included in the terlipressin formulation. Since there is no requirement for Malm to reduce-to-practice each buffer species and Applicant has provided no evidence why benzoate would exhibit distinct properties when compared to acetate, an ordinary skilled artisan would have the requisite expectation of success in substituting benzoate and acetate, or even substituting any other monovalent organic buffer for acetate, without evidence to the contrary. Therefore, contrary to Applicant’s argument, the fact that Malm only reduces-to-practice acetate as the buffer in the terlipressin does not per se preclude a finding of obviousness.
In response to Applicant’s second argument, i.e., Kocherlakota’s teachings teach away from the claimed invention given that Kocherlakota explicitly teaches vasopressin formulations that are free of acetate buffer (See Applicant’s Response received on 4/16/26, pg. 7-8), it is found unpersuasive. Pursuant to MPEP 2123 (II), “[d]isclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). Furthermore, "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). In the instant case, it is acknowledged that Kocherlakota teaches vasopressin formulations that are free of acetate buffer. However, the instant claims do NOT require acetate as the buffer. It is noted that the features upon which applicant relies (i.e., low-concentration acetate buffer) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). It is further noted that new claims 38-39 are not included in this rejection. Since the claimed invention does not require acetate as the buffer in the terlipressin composition of the rejected claims, the teachings of Kocherlakota do not constitute a teaching away from the claimed invention. Thus, contrary to Applicant’s argument, an ordinary skilled artisan would not need to ignore Kocherlakota’s requirement for an acetate-free environment.
In response to Applicant’s third argument, i.e., the addition of an amino acid to the formulations of Malm and selection of a 1-5 mM amino acid concentration is not a matter of routine optimization where a mere overlap in broad ranges does not establish obviousness without a specific reason to select the claimed sub-range (See Applicant’s Response received on 4/16/26, pg. 8), it is found unpersuasive. As an initial matter, it is noted that the rejection does not utilize routine optimization to render the amino acid concentration obvious, but rather an overlapping range rationale. As stated in the rejection supa, MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). However, it is acknowledged that the MPEP refers to optimization when considering disclosure of a very broad range. (emphasis added). MPEP 2144.05(III)(D) states that one factor that may weigh against maintaining an obviousness rejection based on optimization of a variable disclosed in a range in the prior art is where an applicant establishes that the prior art disclosure of the variable is within a range that is so broad in light of the dissimilar characteristics of the members of the range as to not invite optimization by one of skill in the art. Genetics Inst., LLC v. Novartis Vaccines & Diagnostics, Inc., 655 F.3d 1291, 1306, 99 USPQ2d 1713, 1725 (Fed. Cir. 2011) (holding that ordinary motivation to optimize did not apply where disclosure was 68,000 protein variants including 2,332 amino acids where one of skill in the art would appreciate that the claimed truncated proteins vary enormously in structure).
Furthermore, MPEP 2131.03(II) states that in order to anticipate the claims, the claimed subject matter must be disclosed in the reference with "sufficient specificity to constitute an anticipation under the statute." What constitutes a "sufficient specificity" is fact dependent. If the claims are directed to a narrow range, and the reference teaches a broader range, other facts of the case, must be considered when determining whether the narrow range is disclosed with "sufficient specificity" to constitute an anticipation of the claims. Compare ClearValue Inc. v. Pearl River Polymers Inc., 668 F.3d 1340, 101 USPQ2d 1773 (Fed. Cir. 2012) with Atofina v. Great Lakes Chem. Corp, 441 F.3d 991, 999, 78 USPQ2d 1417, 1423 (Fed. Cir. 2006). If the prior art disclosure does not disclose a claimed range with "sufficient specificity" to anticipate a claimed invention, any evidence of unexpected results within the narrow range may render the claims nonobvious (emphasis added). The question of "sufficient specificity" is similar to that of "clearly envisaging" a species from a generic teaching.
In the instant case, the question is whether the prior art’s amino acid concentration range(s) constitute a “broad” range, and if so, does the reference discuss the range with sufficient specificity to render the claimed range obvious where evidence of criticality of the claimed narrower range overcomes a finding of obvious as demonstrating unexpected results. As discussed in the rejection supra, Kocherlakota expressly teaches a specific embodiment of a vasopressin composition comprising about 1.95 mM aspartic acid where such inclusion of an amino acid stabilizer improved the formulation’s shelf-life stability. As such, this specific embodiment taught by Kocherlakota constitutes a specific amino acid concentration species that falls within the claimed amino acid ranges as recited in instant claims 1 and 11-13; and which would anticipate the amino acid limitation if the rejection was one of anticipation. Warne was utilized in order to support a narrower concentration range for other amino acids recited in dependent claims 9, 13, and 33 that function as stabilizers such as methionine. For methionine, Kocherlakota teaches a concentration of 0 mM to 670 mM for methionine (i.e., molar mass is 149.21 g/mol). Warne narrows this range from 0.1 to 50 mM. However, Warne also teaches narrower ranges of about 1 mM to 25 mM (See Warne, claim 17), and utilizes a specific concentration of 10 mM in the Examples (See Warne, Examples 1-8), albeit, in compositions with larger-sized proteins. Even though 10 mM is not encompassed by the instantly claimed concentration range, this concentration amount is at the lower end of Warne’s range of 0.1 to 50 mM. As such, Warne demonstrates that a methionine concentration at the lower end of the concentration range exhibits the improved protein storage stability thereby constituting sufficient specificity that a methionine concentration of 5 mM would exhibit similar properties. Thus, the Examiner asserts that Warne’s range from 0.1 to 50 mM and about 1 mM to 25 mM are not “broad” ranges. Moreover, even if such ranges are considered “broad” ranges, the combination of Kocherlakota demonstrating improved stability of a vasopressin composition containing about 1.95 mM aspartic acid, and Warne demonstrating improved stability of protein compositions containing 10 mM methionine constitute sufficient specificity to render the narrow instantly claimed amino acid concentration range obvious. Furthermore, it is noted that Applicants have not provided any evidence of criticality and/or unexpected results for the instantly claimed concentration range. Therefore, contrary to Applicant’s argument, the teachings of Warne suggest an amino acid concentration range that does not constitute a very broad range, but even if considered a broad range, the combination of Kocherlakota and Warne provide sufficient specificity for an ordinary skilled artisan to reasonably expect an amino acid such as aspartic acid or methionine to improve terlipressin storage stability at a concentration within the claimed range of 1-5 mM, especially given that there has been no evidence of criticality or unexpected results for the claimed range.
In response to Applicant’s fourth argument, i.e., the Office’s reliance on Warne is misplaced because Warne is directed to preventing aggregation in large proteins like antibodies and Factor VIII, and thus, there is no reasonable expectation of success to apply Warne’s teachings to small peptides to prevent storage aggregation (See Applicant’s Response received on 4/16/26, pg. 8-9), it is found unpersuasive. Pursuant to MPEP 2141, “[a] prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983), cert. denied, 469 U.S. 851 (1984). Moreover, pursuant to MPEP 2152.02(b), in order for a prior art document to describe a claimed invention under AIA 35 U.S.C. 102(a)(1) or (a)(2), the prior art document need only describe and enable one skilled in the art to make a single species or embodiment of the claimed invention. See Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1562, 19 USPQ2d 1111, 1115 (Fed. Cir. 1991). In the instant case, it is acknowledged that Warne exemplifies improved protein storage stability for three larger proteins, e.g., an antibody, Factor VIII, and rhIL-II, with the addition of methionine as a stabilizer. However, as discussed in the rejection supra, when considering the teachings of Warne as a whole, it is clear that Warne is not limited to large proteins. More specifically, Warne teaches that the proteins that benefit from the addition of methionine are those known to aggregate or considered likely to aggregate including antibodies, coagulation factors, ligands, enzymes, etc.; for example, a protein within a formulation aggregates during storage, as a result of elevated temperature, or exposure to light (See Warne, [0010], [0019], [0055]). In fact, Warne teaches specific species of proteins that would benefit from the addition of methionine for improved storage stability including small peptides; in particular, insulin A-chain, insulin B-chain, atrial natriuretic factor, calcitonin, and glucagon (See Warne, [0056]). As such, the improved storage stability suggested by Warne by the inclusion of methionine as a stabilizer is not limited to large proteins. Moreover, as evidenced by Glypressin reference and Chawathe et al., terlipressin is susceptible to storage degradation and likely degradation due to light exposure. Thus, contrary to the Applicant’s argument, the Office has provided evidence that an ordinary skilled artisan would have the requisite expectation of success to expect the addition of methionine as a stabilizer to a terlipressin composition to improve the composition’s storage stability.
Accordingly, the rejection of claims 1-3, 6, 9, 11-13, 15, 17-18, 28, 30, and 33-37 is maintained as Applicants’ arguments are found unpersuasive.
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 1-3, 6, 9, 11-13, 15, 17-18, 28, 30, and 33-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24, 26-32, and 34 of copending Application No. 19/185,396 (Jezek et al. US Publication No. 2025/0241981 A1) in view of Malm WO 2019/239386 A1 published on December 19, 2019 (effective filing date of June 15, 2018) (cited in the IDS received on 6/21/21). Please note that the rejection has been updated in light of Applicants’ amendments; namely, addition of new claims 38-39. Jezek et al. claims:
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(See Jezek claims 1-2, 6-9, 13-21, and 23). As such, the ‘396 claimed aqueous solution composition constitutes the instant aqueous solution composition where the therapeutic agent can be terlipressin, the buffer can be acetate (See Jezek claim 11), the amino acid can be methionine, arginine, glycine, or proline, and further comprises mannitol as an uncharged tonicity modifier. The ‘396 concentrations of each component overlap with the instant concentrations of each component. Therefore, the ’396 claimed invention renders obvious instant claims 1-3, 6, 9, 11-13, 15, 17-18, 30, and 33-39.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant’s request to hold the present double-patenting rejection in abeyance until Notification from the Examiner that claims pending in the present Application are deemed allowable is acknowledged. As such, the double-patenting rejection is maintained.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to THEA D' AMBROSIO whose telephone number is (571)270-1216. The examiner can normally be reached M-F 11:00 to 8:00 pm.
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/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654
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