Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim status
The preliminary amendments filed on October 13, 2023 amended claims 4, 7, 8, 10, 12, 14, 17, 19, 23-24, 27-31, 33, 36, 38, 40-41, 43-44, 47, 49-50, 53-54, 57, 61, and 63; canceled claims 32, 34-35, 37, 39, 42, 56, 64 and 65. Consequently claims 1-31, 33, 36, 38, 40-41, 43-55, 57-63 are pending and will be examined on the merits.
Priority
The instant application claims benefit of provisional applications, Application No. 63337523 (filed May 2, 2022). The effective filing date of instant claims 1-31, 33, 36, 38, 40-41, 43-55, 57-63 is May 2, 2022.
Information Disclosure Statement
The information disclosure statement filed on October 19, 2023 and July 24, 2024 comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
It is known in the art that the stability of an antibody liquid formulation can be measured by determining the percentage of antibody that forms an aggregate within the formulation after storage for a defined amount of time at a defined temperature, or under stress conditions (e.g., agitation), wherein stability is inversely proportional to the percent aggregate that is formed (paragraph [0100]).
As evidenced by Cao et al in US20210252146A1 (published in Aug. 2021, “Stable antibody formulation”), antibody in an aggregated form is also denoted as the high molecular weight—HMW—form (page 18, paragraph [0124]) and can be measured by size exclusion chromatography including SE-HPLC and SE-UPLC. Using broadest reasonable interpretation, a person with ordinary skills in the art would interpret the term “HMW species” as “antibody aggregates”. The instant case will be examined accordingly.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
Claims 1-26, 43-47, 49-55 are rejected under 35 U.S.C. 103 as being unpatentable over Dix et al, “Stabilized Formulations Containing Anti-Inerleukin-4 Receptor (IL-4R) Antibodies” (US 2012/0097565 A1, published April 26, 2012), and as evidenced by “Application for Extension of Patent Term Under U.S.C. § 156” (May 23, 2017) for U. S. Patent No. 7,608,693 (US’ 693, Martin et. al, issued Oct. 2009).
Regarding claims 1 and 8-11, Dix et al teach “A pharmaceutical formulation comprising: (i) a human antibody that specifically binds to human interleukin-4 receptor alpha (hIL-4Ra); (ii) a buffer at a pH of 5.9+0.5 pH units; (iii) an organic cosolvent; (iv) a thermal stabilizer, and (V) a viscosity reducing agent.” (Claim 1) and “the organic cosolvent is selected from the group organic consisting of polysorbate 20, poloxamer 181 and polyethylene glycol 3350.” (Claim 9), where the organic cosolvent in claim 9 is at the concentration of about 0.085 to about 1.15% w/v” (claim 10). This formulation matches the antibody and the components of the excipients of the formulation in the instant case, with a PEG and poloxamer range of 0.085-1.15%, which overlaps with the instant claim 1.
According to MPEP2144.05, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. It is well within the abilities of an ordinary artisan to optimize the amount of poloxamers such as Pluronic F68 by picking a concentration at the range of 0.01-0.19% w/v (which overlaps with the range describe in Dix et al claim 10) and combine with other excipients described by Dix et al in claims 1 and 9 and arrive at a formulation claimed in the instant case through no more than routine experimentation.
Regarding claims 2-3, Dix et al teach a human antibody that specifically binds to hIL-4R in the pharmaceutical formulation comprising a heavy chain variable region (HCVR, SED ID NO. 1) and a light chain variable region (LCVR, SED ID NO. 5) with the corresponding HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 that are identical to the HCVR, LCVR sequences (claim 3, instant SEQ ID NO. 1/2) and corresponding HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 sequences (claim 2, instant SED ID No. 3, 4, 5 and 6, 7, 8) of the instant case.
Regarding claims 4-6, Dix et al. further teach that the IL-4Ra antibody contains heavy chain constant region (paragraph [0053]) that can be either IgG1 (paragraph [0083]) or IgG4. Applicants recite in paragraph [0057] “Exemplary anti-hIL-4Ra antibodies that may be included in the pharmaceutical formulations of the present invention are set forth in U.S. Pat. No. 7,608,693 which include both IgG1 or IgG4 (Col. 1, Line 51 of US ‘693) antibodies (eg. SEQ ID NO. 272-273 of US ‘693, col. 10, line 46).
Regarding claim 7 that limits the full antibody sequences to SEQ ID No. 9/10, it is obvious for an ordinary artisan to construct an antibody by combining the HCVR/LCVR (SEQ ID NO.1/2) region with corresponding constant regions of Hc and Lc of human IgG4, as taught by Dix et al, which reads to Dupilumab (a human IgG4 antibody), the active ingredient of an FDA approved product, Dupixent, with original HCVR/LCVR sequences disclosed in US’ 693 (Martin et al Oct 2009). SEQ ID NO. 9 and 10 show 100% sequence identity to the full Hc and Lc sequences of dupilumab, as evidenced by “Application for Extension of Patent Term Under U.S.C. § 156” (May 23, 2017, Regeneron Pharmaceuticals):
Amino acid sequence alignment of SEC ID NO. 9 with Dupilumab Heavy chain:
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526
579
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Amino acid sequence alignment of SEQ ID No.10 (query) with Dupilumab Light chain:
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374
734
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Regarding claims 12-16 that are drawn to the buffer components and concentration range in claim 1, Dix et al teach in paragraph [0014] the liquid pharmaceutical formulation contains two buffers where in a specific embodiment, the first buffer is an acetate buffer and the second buffer is a histidine buffers. In one specific embodiment, the acetate is at a concentration of 12.5 mM ± 1.9 mM, which meets the limitation of 10-15mM in claim 13, and the histidine is at a concentration of 20 mM ±3 mM, which meets the limitation of 15-25mM in claim 15. In another embodiment taught by Dix et al, in paragraph [0078], the buffer system comprises acetate at about 12.5 mM and histidine at about 20 mM, at a pH of about 5.9, which falls into the acetate range in claim 14 and the histidine range in claim 16.
Regarding claims 17-18 that are drawn to the thermal stabilizer sucrose and its concentration range in claim 1, Dix et al teach in claim 16 that the thermal stabilizer is sucrose at a concentration of 5% ± 0.75%, which meets the limitations in claims 17-18.
Regarding claims 19-22 that are drawn to the viscosity modifier arginine and its concentration range in claim 1, Dix et al discovered (paragraph [0094]) that low to moderate viscosity liquid formulations comprising high concentrations of an anti-hIL-4Ra antibody can be obtained by formulating the antibody with arginine from about 25 mM to about 100 mM, and disclose a series of embodiments containing arginine at a concentration of about 25mM ±3.75 mM, about 50 mM ±7.5 mM, or about 100 mM±15mM, about 20 mM to about 30 mM, about 21 mM to about 29 mM, about 21.25 mM to about 28.75 mM, about 22 mM to about 28 mM, about 23 mM to about 27 mM or about 24 mM to about 26 mM (paragraph [0080], which meet the limitations of claims 19-22.
Regarding instant claims 23-26 that are drawn to the amount of antibodies in claim 1, Dix et al teach hIL-4Ra antibody range of 110±11 mg/mL to about 190±19 mg/mL and embodiments that contain “… about 100 mg/mL, about 175 mg/mL, or about 200 mg/mL of an antibody” (paragraph [0068]), which meet the antibody ranges in these claims.
Regarding instant claims 43-47 and 49, Dix et al teach in claims 23-26 a glass vial, or a syringe, or a syringe comprising a fluorocarbon-coated plunger or a low tungsten syringe can contain the antibody formulation discussed above. Dix et al further teach in paragraph [0101] an embodiment wherein “the liquid pharmaceutical formulation is administered subcutaneously in a volume of approximately 1 ml ± 0.15 ml from a prefilled syringe or in an autoinjector. In another embodiment, the formulation is administered in a volume of between about 1 ml and 2.5 ml from a microinfuser device. The formulation may be prefilled in a pouch or a cartridge for use in the microinfuser”, suggesting that the liquid formulation can be contained in a large volume device or bolus injector.
Claims 50-53 are drawn to delivery devices or containers of the stable liquid formulation in claim 1.
Dix et al teach under “Containers for the pharmaceutical formulations and methods of administration” that the pharmaceutical formulation discussed above may be “contained within any container suitable for storage of the medicines, including any types of syringes that can be used to contain or administer the formulation” (page 10, paragraph [0095]). Dix et al gave examples of reusable pen or autoinjector delivery devices as well as disposable pen or autoinjector delivery devices (page 10, paragraph [0099]).
Claims 54 and 55 that are drawn to kits comprising (i) a container containing the stable liquid pharmaceutical formulation of claim 1 and (ii) labeling for use of the pharmaceutical formulation.
The following is a citation from MPEP211.05:
“To be given patentable weight, the printed matter and associated product must be in a functional relationship. A functional relationship can be found where the printed matter performs some function with respect to the product to which it is associated. See Lowry, 32 F.3d at 1584, 32 USPQ2d at 1035 (citing Gulack, 703 F.2d at 1386, 217 USPQ at 404).” “where the printed matter and product do not depend upon each other, no functional relationship exists. For example, in a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals. In re Ngai, 367 F.3d at 1339, 70 USPQ2d at 1864” The labeling in claims 54 and 55 provides instructions for using the formulation in the container, which is not related to the formulation in the container, therefore there is no functional relationship between the labeling and the liquid formulation in the container.
Since no patent weight is given to the labeling in claims 54 and 55, the content of these claims is identical to that of claim 53 which recites a container of the formulation, therefore these claims are rejected accordingly as discussed above.
Claims 27-29, 31, 33 and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Dix et al (US 2012/0097565 A1, published April 26, 2012), as applied to claim 1, in view of Grapentin et al. "Protein-polydimethylsiloxane particles in liquid vial monoclonal antibody formulations containing poloxamer 188." Journal of pharmaceutical sciences 109.8 (2020): 2393-2404. (published March 2020), and as evidenced by Usach et al. "Subcutaneous injection of drugs: literature review of factors influencing pain sensation at the injection site." Advances in therapy 36.11 (2019): 2986-2996.
Claim 27 is drawn to “A stable liquid pharmaceutical formulation comprising: (i) a human antibody at a concentration of 150 mg/mL ± 10 mg/mL, wherein the antibody specifically binds to human interleukin-4 receptor alpha (hIL-4Ra) and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 12.5 mM ± 1.25 mM; (iii) histidine at a concentration of 20 mM ± 2 mM;(iv) sucrose at a concentration of 5% w/v ± 0.5% w/v; (v) arginine at a concentration of 25 mM ± 2.5 mM; and (vi) a surfactant comprising PEG3350 or poloxamer 188 at a concentration of from 0.01% w/v to 0.19% w/v, wherein the formulation has a pH of 5.9 ± 0.2.”
Dix et al teaches “Formulation A” (paragraph [0117]), a liquid formulation containing 25 mM arginine, 20 mM histidine, 12.5 mM acetate, 5% (w/v) sucrose, 0.2% (w/v) Polysorbate 20, and 150 mg/mL mAb1 (bearing identical HCVR/LCVR as in claim 27, paragraph [0065]), at pH 5.9, that represents an optimized formulation having a low viscosity (about 8.5 cBoise) and being physiologically isotonic (about 293 mOsm/kg), while maintaining the stability of mAb1. “Formulation A” reads to all limitations in the formulation in claim 27 of the instant case except the surfactant comprising PEG3350 or poloxamer 188 at a concentration of from 0.01 to 0.19%w/v.
Dix et al teach the effect of organic cosolvents including PEG 3350, PEG 300 PLURONIC F68 and Propylene Glycol (20%) on the stability of mAb1 at 15mg/ml in the formulation (paragraph [0106]). Among them, the effect of Pluronic F68 (poloxamer 188, CAS registry number 691397-13-4) (Dix et al states Pluronic F68 to be poloxamer 181, which appear to be a typographical error) at 0.2% w/v is similar to polysorbate 20 at 0.2% w/v on mAb1 stability upon agitation stress (Table 1, paragraphs [0106] [0107]) and thermal stability (Table 2, paragraphs [0106] [0108]). Dix et al further teach poloxamer 188 concentrations that falls within the range of claim 27 (paragraph [0072]), suggesting that poloxamer 188 can be an alternative surfactant in the liquid formulation in their invention. However, Dix et al do not teach a specific formulation that contains poloxamer 188 at a range of 0.01-0.19% w/v.
Grapentin et al (2020) teach that a motivation of using poloxamer 188 to substitute polysorbate 20 in an antibody pharmaceutical liquid formation exists: “Surfactants used in marketed parenteral therapeutic protein formulations are limited to 3 nonionic molecules: polysorbates 20 (PS20) and 80 (PS80), and poloxamer 188 (P188). Although widely used within commercial mAb drug products (page 2394, column 1, paragraph 2), polysorbates can degrade via oxidative and hydrolytic pathways and issues stemming from polysorbate degradation have become widespread throughout the industry. It is desirable to identify and use alternative surfactants with less degradation liabilities for parenteral protein formulations.” (page 2397, column 1, paragraph 4). Grapentin et al recites poloxamers as more chemically stable than polysorbates, with little degradation under relevant formulation and storage conditions (page 2394, column 2, paragraph 1). Grapentin et al compared poloxamer 188, polysorbate 20 or 80 at 0.02-0.07% (w/v) in formulations of four mAbs of 2 sub-classes, IgG1 and IgG4, with protein concentrations up to 150 mg/mL (Table 1) for stability under recommended storage and stress conditions using the particle and antibody aggregate read-out (page 2397, column 2, paragraph 2). Results in Figure 1 show that poloxamer 188 provided equal or better stabilizing properties for the 4 mAbs compared to PS 20 at different storage conditions (Figure 1A) with regards to visible particles and sub-visible particle counts (Figure 1B).
Therefore, it would have been obvious for a person with ordinary skill in the art to substitute polysorbate 20 in Formulation A taught by Dix et al with poloxamer 188 at a concentration within 0.01% w/v to 0.19% w/v and expect poloxamer 188 to provide protection comparable to polysorbates under storage and stress conditions, even at high antibody concentrations, before the effective filing date of the instant case.
Regarding claim 28 that limits the antibody concentration to 175mg/ml, Dix et al teach a Formulation D (Table 7) of mAb1 at 175mg/ml (with 20mM histidine, 12.5mM acetate, 50mM arginine, 5% w/v sucrose), which has similar viscosity (~9.5 cBoise) and higher osmolarity (~370 mOsm/kg) than Formulation A that contains mAb1 at 150mg/ml, which are within the acceptable range for parenteral administration without pain, as evidenced by Usach et al (2019) (page 1, column 2, paragraph 1). Therefore, one with ordinary skills in the art would expect predictable results with acceptable properties when the antibody concentration in claim 27 increase to 175mg/ml at the time of the invention.
Claim 29 limits the antibody in claims 27 and 28 to an IgG4 antibody, bearing full antibody Hc/Lc sequences (SEQ ID NO. 9/10), which reads to Dupilumab, the antibody in claim 7, as discussed above.
It would have been obvious for a person with ordinary skills in the art to use Dupilumab in “Formulation A” taught by Dix et al and substitute polysorbate 20 with poloxamer 188 at the concentration of 0.02-0.07% (w/v) as taught by Grapentin et al which is within the range of 0.01-0.19% w/v in claim 29, with reasonable expectation of success.
Claims 31, 33 and 41 are drawn to the stability of the liquid formulation in claim 1 upon agitation or exposure to high temperature at 45oC.
Claim 1 and the teaching of Dix et al regarding claim 1, are discussed above.
Regarding claims 31 and 33, Dix et al teach in paragraph [0107] and Table 1, after vortexing for about 120 minutes 0.3 ml of 15 mg/ml of mAb1 in 10 mM phosphate, pH 6.0, and Pluronic F68 (poloxamer 188) in a 2 ml glass vial, 1.7% mAb1 was aggregated as determined by size exclusion chromatography. Dix et al further teach that the same antibody formulation has 5.1% aggregated antibody after being kept at about 45° C for about 28 days (paragraph [018] and Table 2). Dix et al further teach that mAb1 was most stable in a formulation containing both histidine and acetate at approximately pH 5.9 (paragraph [0115], Table 6).
Combining the teachings of Dix et al and Grapentin et al, it would have been obvious for a person with ordinary skills in the art to predict that an antibody formulation containing the two buffers (acetate and histidine) at a pH of 6.0 and poloxamer 188 at 0.01-0.19% w/v, after vortexing for up to 120 minutes at room temperature, to have HMW species close to 1.7%, which is lower than 3% in claim 31; and to have HMW species of about 5.1% after storage at 45°C for about 30 days, which is lower than 8% in claim 33, before the effective filing date of the instant application.
Regarding claim 41 which limits the amount of HMW species determined by SE-UPLC following agitation of an antibody formulation in claim 1 for 24 hours at 25oC, Dix et al teach that when compared with a “starting material” in the absence of vortexing (paragraphs [0107-0108], Tables 1-2) that has 1.8% aggregated mAb1, the formulation containing 0.2% pluronic F68 (poloxamer 188) showed no increase in antibody aggregates after being vortexed for 120 minutese.
Dix et al do not teach stability upon longer agitation stress.
Grapentin et al teach a study on “the impact of interfacial stress” wherein the antibody formulations were subjected to agitation at 5oC or 25oC for 7 days. (page 2395, col. 1, paragraph 2). The antibody formulations for mAb 1-4 containing poloxamer 188 at 0.02-0.07% (w/v) under these stress conditions had 0-0.3% increase in HMW species (Figure 1c).
Based on the teachings of Dix et al and Grapentin et al, one with ordinary skills in the art would expect the level of the initial HMW % of an antibody formulation in claim 1 to be about 2% (close to 1.8% in the starting material taught by Dix et al) and the increase of HMW species to be within 0.3% after agitation for 24 hours since it is a much shorter agitation than 7 days of agitation tested by Grapentin et al, therefore the HMW species % in resultant formulation would be around 2.3%, lower than 4% in claim 41.
Claims 30, 36, 38 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Dix et al (US 2012/0097565 A1, published April 26, 2012), as applied to claim 1, in view of Grapentin et al. (2020): 2393-2404. (published March 2020), and in further view of Bak et al., “Process for reducing subvisible particles in a pharmaceutical formulation”, US10342876 (2019).
Claim 1 and the teaching of Dix et al and Grapentin et al regarding claim 1 is discussed above.
Claim 30 is drawn to a phospholipase protein in the antibody formulation in claim 1.
Claims 36 and 38 are drawn to the amount of SVP (subvisible particles, having a diameter of ≥10 mm) or particles (≥25 mm) in an antibody formulation containing a phospholipase protein, respectively.
Claim 40 is drawn to a phospholipase protein in the antibody formulation in claim 36.
Dix et al do not teach a phospholipase protein or SVP in an antibody formulation.
Grapentin et al do not teach a phospholipase protein.
However, Bak et al teach an antibody formulation in Examples 3 (page 13, col. 2, paragraph 2, Table 4) and 5 (page 14, col. 2, paragraph 1, Table 4) that contain 20 mM histidine (pH 5.9 ), 12.5 mM acetate , 0.02 % polysorbate 20, 5 % sucrose (w/v), 25mM arginine, and 150 mg/ml antibody, stored as 2.5ml in a 3 ml glass vial wherein the polysorbate 20 quantity decreases (page 14, col. 1 paragraphs 1 and 2, Tables 5 and 6) while the amount of subvisible particles (SVP as measured by HIAC or MFI, which is microscopy based) increases (page 13, col. 2 paragraphs 1 and 2, Tables 3 and 4) during the storage of the antibody formulation. Samples with PS20-B listed in Table 4 showed 175 and 108 SVP (≥10 mm) after 6 months of storage at 5oC (Table 4, page 13, col.2 paragraph 2). Bak et al further teach that in these antibody formulations where the antibody is produced in a mammalian cell line such as CHO cells (Example 5, page 14, col.2, paragraph 1), the agent responsible for polysorbate 20 degradation is phospholipase B-like 2 protein (PLBL2), the abundance of which correlated with the amount of polysorbate degradation activity (page 17, col. 2 paragraph 2, Figure 2 ant Table 13).
Regarding the amount of subvisible particles (SVP, ≥10 mm) and particles (≥25 mm) in the antibody formulation in claims 36 and 38, Grapentin et al teach the testing of antibody formulations in 2.4 mL (close to 2.25ml volume in claims 36 and 38) in 6R Fiolax glass type I vials (page 2394, col.2, paragraph 3): After 12 month of storage at 5°C, substitution of polysorbate 20 by poloxamer 188 at 0.02-0.07% (w/v) in 3 antibody formulations (mAbs 1, 2, 3) exhibits low SVP value of 1-11 (Figure 1b, page 2398), well below the particle numbers in claim 36. In addition, the number of total particles (≥25 mm) in poloxamer 188 formulation of 3 antibodies (mAbs 5, 6, 7) were mostly between 0-50 after storage at 5°C for 12 months (page 2398, col.2, paragraph 1; page 2401, Figure 4a), well below the numbers in claim 38.
Based on the teaching of Dix et al, Grapentin et al and Bak et al, it would be obvious for a person with ordinary skills in the art to modify the formulation taught by Dix et al by using poloxamer as discussed above and to predict that the modified formulation, wherein the antibody is produced from a mammalian cell line, contains a phospholipase protein that is a phospholipase B-like 2 protein, and that the formulation comprises no more than 150 particles having a diameter of >10 mm and no more than 50 particles having a diameter of ≥25 mm in a volume of 2.25 mL after storage for 6 months at 5°C.
Claims 48 and 63 are rejected under 35 U.S.C. 103 as being unpatentable over Dix et al, as applied to claims 1, 44 and 47, in view of Hu et al, “Stabilized formulations containing anti-IL-33 antibodies”, US2020/0297845 A1, US’845, September 2020).
Claims 48 and 63 further limit the device containing the liquid formulation in claim 1 to be a prefilled staked needle syringe or a safety system delivery device, respectively.
Claims 1 and the teaching of Dix et al regarding claim 1, are discussed above.
Dix et al do not teach a prefilled staked needle syringe or a safety system delivery device.
However, Hu et al US’845 teach that a stable liquid antibody formulation can be contained in a prefilled syringe, or a prefilled staked needle syringe (claim 52) or a safety system delivery device (claim 67). He et al. recite that “safety system devices can be relatively inexpensive, and operate to manually or automatically extend a safety sleeve over a needle once injection is complete.” [0112]
Therefore, it would have been obvious for a person with ordinary skills in the art to use a prefilled staked needle syringe with the liquid formulation in claim 1 for its advantage of convenience, accurate dosing and reduced contamination risk or to utilize the safety system device taught by Hu et al to contain the liquid pharmaceutical that can provide inexpensive and safe operation of an injection.
Claims 57-62 are rejected under 35 U.S.C. 103 as being unpatentable over Dix et al, as applied to claim 1, in view of the Dupixent label from U.S. Food and Drug Administration which was available on line on Oct 27, 2021.
Claims 57-62 are drawn to unit dosage forms of the liquid pharmaceutical formulation in claim 1.
Claim 1 and the teachings of Dix et al regarding claim 1 are discussed above.
Dix et al do not teach unit dosage of the liquid pharmaceutical formulation in claim 1.
However, the FDA Dupixent label (Oct. 27, 2021) teaches the unit dosage of the active ingredient of Dupixent, Dupilumab, which reads on the antibody in claim 1, at 100mg, 200mg and 300mg, all within 1-500mg range can be used to treat patients and the liquid formulation at these dosages are contained in a prefilled syringe, as discussed above.
Therefore, it would have been obvious for a person with ordinary skills in the art to obtain a formulation in claim 1 as discussed above and apply the same unit dosage forms taught by the FDA Dupixent label, which meets the limitations in claims 57-62.
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.
US Patent No. 8945559 (US’559)
The instant application and the reference patent US’559 are commonly assigned to Regeneron Pharmaceuticals, Inc. Claims 1-31, 33, 36, 38, 40-41, 43-55, 57-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over US’559.
Instant claims 1-7, 10-13, 15, 17, 19-26, 28, 41, 44-46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3, 10, 11, 16, 18, 19, 23, and 24 of US’559 in view of Grapentin et al (2020), as evidenced by “Application for Extension of Patent Term Under U.S.C. § 156” (May 23, 2017) for U. S. Patent No. 7,608,693 (Martin et. al, issued Oct. 2009).
Regarding instant claims 1-7, 12-13, US’559 claim 1 teaches: A stable pharmaceutical formulation comprising:
(i) a human antibody at a concentration of from 100 mg/ml to 200 mg/ml, wherein the antibody specifically binds to human interleukin-4 receptor alpha (hIL-4Rα) and comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:5;
(ii) acetate at a concentration of from 10 mM to 15 mM;
(iii) histidine at a concentration of from 15 mM to 25 mM;
(iv) sucrose at a concentration of from 2.5% w/v to 10% w/v;
(v) polysorbate at a concentration of from 0.1% w/v to 0.3% w/v; and
wherein the formulation has a pH of from 5.6 to 6.2.
The antibody in claim 1 US’559 bears identical HCVR/LCVR (SEQ ID No. 1/2) pairs (therefore contains identical HCDRs and LCDRs, SEQ ID No. 3, 4, 5 and SEQ ID No. 6, 7, 8) to the antibody in claims 2 and 3 of the instant application and are interpreted as full antibody that contains heavy chain constant region based on the specification of US’559.
Claim 1 US’559 reads to the antibody concentration range, buffers (acetate and histidine), thermal stabilizer (sucrose), viscosity modifier (arginine) and a pH range of 5.7-6.1 (significantly overlaps with pH 5.6-6.2), of instant claims 1, 12, 13, 15, 17, 24, with identical or significant overlapping ranges.
However, claim 1 US’559 does not teach a surfactant comprising a polyethylene glycol or a poloxamer at a concentration of 0.01-0.19% w/v.
Grapentin et al (2020) teach suitability and motivation of substituting polysorbate with poloxamer 188 as discussed above.
Therefore, it would have been obvious for an ordinary artisan to substitute polysorbate in the stable pharmaceutical formulation of claim 1 US’559 with poloxamer at a concentration of at 0.01-0.19% w/v and adjust pH to a range 5.7-6.1 to arrive at the formulation in claims 1-4, 10-13, 15, 24 of the instant case.
Regarding instant claims 5-7, since the antibody in US’559 is interpreted as a full antibody that contains heavy chain constant region, one with ordinary skills in the art would consider using IgG1 or IgG4 which are broadly used in the pharmaceutical industry. The antibody with the indicated HCVR/LCVR and IgG4 constant regions reads to the antibody in claim 7 of the instant case, with SEQ ID No. 9 (Hc) and 10 (Lc) having 100% sequence identity with Dupilumab, the active ingredient of the FDA approved medicine, Dupixent, as discussed above.
Regarding instant claims 19-22, claims 1, 10, 11 of US’559 recite the viscosity modifier arginine with overlapping ranges in these claims.
Regarding instant claims 23-26, claims 1, 2 and 3 of US’559 recite the antibody concentrations or concentration ranges that read to the antibody concentrations in these claims.
According to MPEP2144.05, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. It is well within the abilities of an ordinary artisan to optimize the amount of arginine, antibody concentration in the formulation in claim 1 of US’559 and arrive at the concentrations claimed in the instant case through no more than routine experimentation.
Instant claims 14, 16, 18, 27-29, and 57-62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 9, 20, 23, 24 of US’559 in view of Grapentin et al (2020), and in further view of Dupixent, an FDA approved medicine (Dupixent label, Oct 2021).
Instant claims 14, 16, 18 are drawn to concentration ranges of acetate, histidine and sucrose that are within the range of claim 1 and/or claim 9 of US’559.
Instant claims 27 to 28 are drawn to specific stable pharmaceutical antibody formulations with narrow concentration range of the antibody, excipient, pH range that are within the ranges in claims 20, 23-25 of US’559, except the surfactant, which is polysorbate 20 or 80 at 0.2± 0.03% w/v in US’559, as opposed to PEG3350 or poloxamer 188 at a concentration of 0.01-0.19% w/v in the instant case. Claim 29 is drawn to the corresponding formulations in claim 27 and 28 when the antibody in these formulations is Dupilumab (IgG4).
Claims 20, 23-25 of US’559 teach formulations with narrow ranges of antibody and excipients that significantly overlaps with the corresponding ranges in instant claims 14, 16, 18 and 27-29.
According to MPEP2144.05, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. It is well within the abilities of an ordinary artisan to optimize the amount of arginine, antibody concentration in the formulation in claims 20, 23-25 of US’559 and arrive at the concentrations claimed in the instant case through no more than routine experimentation.
Combining the teaching of Grapentin et al as discussed above, it would have been obvious for one with ordinary skills in the art to substitute the polysorbate 20 or polysorbate 80 in claims 20, 23-25 of US’559 with poloxamer 188 and obtain the formulation in claim 27-29 of the instant case with predictable results.
Instant claims 57-62 are drawn to unit dosage forms of the liquid pharmaceutical formulation in claim 1.
Claim 1 and the teachings of US’559 and Grapentin et al (2020) regarding claim 1 are discussed above.
US’559 or Grapentin et al do not teach unit dosage of the liquid pharmaceutical formulation in claim 1.
However, the FDA Dupixent label (Oct. 27, 2021) teaches the unit dosages of Dupilumab, which meet the limitations in instant claims 57-62, as discussed above.
Therefore, it would have been obvious for a person with ordinary skills in the art to obtain a formulation in instant claim 1 as discussed above and apply the same unit dosage forms taught by the FDA Dupixent label.
Instant claims 8 and 9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 of US’559 in view of Dix et al (“STABILIZED FORMULATIONS CONTAINING ANTIINTERLEUKIN-4 RECEPTOR (IL-4R) ANTIBODIES”, JP,2016-166218,A, published Sept 2016, here in JP’218).
Instant claims 8 and 9 are drawn to the surfactant in claim 1 to be a polyethylene glycol and PEG3350.
Claim 1 and the teaching of US’559 regarding claim 1, are discussed above.
US’559 does not teach polyethylene glycol in the antibody formulation.
However, JP’218 teach a stable liquid formulation comprising (a) a human IL-4Ra antibody and (b) acetic acid salt at a concentration of 10-15 mM; (c) histidine at a concentration of 15-25 mM; (d) sucrose at a concentration of 2.5-10 (w/v)%; (d) polysorbate at a concentration of 0.1-0.3%(w/v); and (f) arginine at a concentration of 20-100 mM, of which pH is 5.6-6.2. (claim 1) and the organic co-solvent is selected from the group consisting of polysorbate 20, poloxamer 181 and polyethylene glycol 3350 (claim 8) and present at a concentration of about 0.085% to about 1.15% w/v (claim 9), which overlaps with the range of surfactant of polyethylene glycol at a concentration of 0.01-.019% w/v in claim 1 of the instant case.
According to MPEP2144.05, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. It is well within the abilities of an ordinary artisan to optimize the amount of PEG 3350 and pick a concentration within 0.01-0.19% w/v and combine with other excipients described by Dix et al in claims 1 and 9 and arrive at a formulation claimed in the instant case through no more than routine experimentation.
Therefore, it would have been obvious for an ordinary artisan to utilize a polyethylene glycol such as PEG3350 as a surfactant to replace the polysorbate in claim 1 of US’559 at a concentration of 0.01-0.19%w/v to obtain the formulation in claims 8 and 9 of the instant case with reasonable expectation of success.
Claims 31, 33, 41, 50-55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 14 and 22 of US’559 in view of Grapentin et al (2020) and in further view of JP’218).
Claim 1 and the teaching of US’559 and Grapentin et al regarding claim 1, are discussed above.
Instant claims 31, 33 and 41 are drawn to the stability of the liquid formulation in claim 1 upon agitation or exposure to high temperature at 45oC.
US’559 does not teach stability of the antibody formulation when subjected to agitation. Claim 14 of US’559 teach at least about 90% of the native form of the antibody in the formulation in claim 1 US’559 is recovered after about eight weeks of storage at about 45°C. However, US559 does not explicitly teach stability when an antibody formulation is maintained at 45oC for a month.
However, regarding instant claim 31, JP’218 teach in paragraph [0107] and Table 1, after vortexing 0.3 ml of 15 mg/ml of an IL-4R antibody in 10 mM phosphate, pH 6.0, and Pluronic F68 (poloxamer 188) in a 2 ml glass vial for about 120 minutes, 1.7% antibody was aggregated as determined by size exclusion chromatography and there is about 1.8% aggregated antibody in the starting material. Regarding instant claim 33, JP’218 further teach that the same antibody formulation has 5.1% aggregated antibody after being kept at about 45° C for about 28 days (paragraph [0109] and Table 2).
Regarding instant claim 41, Grapentin et al teach a study on “the impact of interfacial stress” wherein the antibody formulation vials described in Table 1 (page 2394) were subjected to agitation on a horizontal shaker at a constant 200 rounds per minute, protected from direct light, at 5oC or 25oC for 7 days. (page 2395, col. 1, paragraph 2). The antibody formulations containing poloxamer 188 at 0.02-0.07% (w/v) under this stress condition had 0-0.3% increase in HMW species (Figure 1c).
Based on the teaching of US’559, Grapentin et al and JP’218, it would have been obvious for a person with ordinary skills in the art to modify the antibody formulation taught by US’559 by replacing the polysorbate with poloxamer 188 at 0.01-0.19% w/v and predict that the modified antibody formulation after vortexing for up to 120 minutes at room temperature to have HMW species (antibody aggregate) close to 1.7%, which is lower than 3% in claim 31; and to have HMW species of about 5.1% after storage at 45° C for about 28 days, which is lower than 8% in claim 33 compared to the starting material, and to expect the level of the initial HMW % in the antibody formulation to be about 2% and the increase of % in HMW species to be within 0.3% after agitation for 24 hours since it is much shorter than 7 days tested by Grapentin et al, and a % of HMW species to be around 2.3% after agitation of the antibody formulation for 24 hours at 25oC, which is lower than 4% in claim 41, before the effective filing date of the instant application.
Instant claims 50-53 are drawn to delivery devices or containers of the stable liquid formulation in claim 1. Claims 54 and 55 are considered duplicate claims of claim 53 and are objected to as discussed above.
Instant claim 1 and the teaching of US’559 and Grapentin et al regarding claim 1 are discussed above
US’559 does not teach pen or autoinjectors.
However, JP’218 teach that “A number of reusable pen or autoinjector delivery devices may be used to deliver the pharmaceutical formulations of the invention”. JP’218 teach examples of reusable pen or autoinjector delivery devices as well as disposable pen or autoinjector delivery devices (page 30, paragraph [0099]).
Therefore, it would have been obvious for an ordinary artisan to utilize these devices or containers taught by JP’218 to contain a liquid pharmaceutical formulation that is modified from the formulation in claim 1 of US’559 by using a surfactant such as poloxamer 188 at 0.01-0.19% w/v taught by Grapentin et al.
Instant claims 30, 36, 38 and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of US’559 in view of Grapentin et al. (2020), and in further view of BAK et al. (2019).
Instant claim 1 and the teaching of US’559 and Grapentin et al regarding claim 1 is discussed above.
Instant claim 30 is drawn to a phospholipase protein in the antibody formulation in claim 1.
Instant claims 36 and 38 are drawn to the amount of SVP (subvisible particles) or particles having a diameter of ≥25 mm in an antibody formulation containing a phospholipase protein, respectively.
Instant claim 40 is drawn to a phospholipase protein in the antibody formulation in claim 36.
US’559 does not teach a phospholipase protein or SVP in an antibody formulation.
Grapentin et al do not teach a phospholipase protein.
However, Bak et al teach the existence of a phospholipase B-like 2 protein (PLBL2, a phospholipase) in an antibody formulation where the antibody is produced in a CHO cell host, the abundance of which correlates with the amount of polysorbate degradation activity as discussed above (See 103 rejection).
The teaching of Grapentin et al regarding the amount of particles (subvisible particles or SVP) having a diameter of ≥10 mm and particles (≥25 mm) in the antibody formulation after storage for 6 months at 5°C is discussed above.
Based on the teaching of US’559, Grapentin et al and Bak et al, it would have been obvious for a person with ordinary skills in the art to predict that after replacing the surfactant in claim 1 of US’559 with poloxamer 188 at 0.01-0.19% w/v, the resultant stable liquid pharmaceutical formulation would contain a phospholipase protein that is a phospholipase B-like 2 protein and that the formulation comprises no more than 150 particles having a diameter of >10 mm and no more than 50 particles having a diameter of ≥25 mm in a volume of 2.25 mL after storage for 6 months at 5°C.
Instant claims 43-49 and 63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 15, 16, 18 and 19 of US’559 in view of Grapentin et al. (2020), as applied to claims 43-46 and 49, and in further view of Hu et al US’845 (2020), as applied to claims 47-48 and 63.
Claim 1 and the teaching of US’559 and Grapentin et al regarding claim 1, are discussed above.
Instant claims 43-49 are drawn to the liquid formulation in claim 1 contained in various container or devices. Claims 15, 16,18, 19 of US’559 teach the devices identical to those in instant claims 43-46. Regarding claim 49, claim 17 of US’559 teach a microinfusor which is considered a large volume device or bolus injector.
Regarding instant claims 47, 48, and 63, US’559 does not teach prefilled syringe or prefilled staked needle syringe. However, Hu et al US’845 teach prefilled syringe or prefilled staked needle syringe and safety system delivery device that are used to contain a similar antibody formulation.
Therefore, it would have been obvious for an ordinary artisan to use poloxamer 188 at 0.01-0.19% w/v in the formulation taught by US’559 and Grapentin et al and put it in the devices described in claims 43-49 and 63 to serve different purpose of the modified formulation.
US Patent No. 9238692 (US’692)
Instant claims 1-31, 33, 36, 38, 40-41, 43-55, 57-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over US’692.
Instant claims 1-7, 10-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11-22 of US’692 in view of Grapentin et al (2020).
Regarding instant claims 1-26, claim 1 of US’692 teaches: A pre-filled syringe composition comprising a liquid pharmaceutical formulation, wherein the liquid pharmaceutical formulation comprises:
(a) 100±10 mg/mL to 200±20 mg/mL of an antibody or antigen-binding fragment thereof that specifically binds human interleukin-4 receptor alpha (hIL-4Rα), wherein the antibody comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:5;
(b) 10 mM to 15 mM acetate;
(c) 15 mM to 25 mM histidine;
(d) 2.5% w/v to 10% w/v sucrose;
(e) 0.1% w/v to 0.3% w/v polysorbate; and
(f) 20 mM to 100 mM arginine;
wherein said liquid pharmaceutical formulation has a pH of from 5.6 to 6.2 and is contained within a syringe.
The antibody in claim 1 US’692 bears identical HCVR/LCVR (SEQ ID No. 1/2) pairs (therefore contains identical HCDRs and LCDRs, SEQ ID No. 3, 4, 5 and SEQ ID No. 6, 7, 8) to the antibody in instant claims 2 and 3 and are interpreted as full antibody that contains heavy chain constant region based on the specification of US’692.
Claims 1, 11-13, 17-18 of US’692 recite concentrations of antibody, buffers (acetate and histidine), thermal stabilizer (sucrose), viscosity modifier (arginine) and pH range of 5.6-6.2 that read to the corresponding components except the surfactant in instant claims 1-26, with identical or significant overlapping ranges.
US’692 does not recite a surfactant comprising a polyethylene glycol or a poloxamer at a concentration of 0.01-0.19% w/v.
However, Grapentin et al (2020) teach suitability and motivation of substituting polysorbate with poloxamer 188 in an antibody pharmaceutical formulation as discussed above.
According to MPEP2144.05, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. It is well within the abilities of an ordinary artisan to optimize the amount of antibody, sucrose, arginine, and pH in the formulation described in claim1 of US’692 and arrive at the concentrations claims 1-26 in the instant case through no more than routine experimentation.
Therefore, it would have been obvious for an ordinary artisan to substitute polysorbate in the stable pharmaceutical formulations in US’692 with poloxamer at a concentration of 0.01-0.19% w/v and adjust the concentration of other components and pH to arrive at the formulation in claims 1-26 of the instant case.
Instant claims 27 to 28 are drawn to specific stable pharmaceutical antibody formulations with narrow concentration range of the antibody, excipient, pH ranges that significantly overlap with the narrow ranges in claims 19-22 of US’692, except the surfactant, which is polysorbate 20 or 80 at 0.2± 0.03% w/v in US’692, as opposed to PEG3350 or poloxamer 188 at a concentration of 0.01-0.19% w/v in the instant case. Claim 29 is drawn to the corresponding formulations in claim 27 and 28 when the antibody in these formulations is Dupilumab (IgG4).
According to MPEP2144.05, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. It is well within the abilities of an ordinary artisan to optimize the amount of antibody concentration and exipients in the formulation in claims 19-22 of US’692 and arrive at the concentrations claimed in the instant case through no more than routine experimentation.
Combining the teaching of Grapentin et al as discussed above, it would have been obvious for one with ordinary skills in the art to substitute the polysorbate 20 or polysorbate 80 in claims 20, 23-25 of US’692 with poloxamer 188 and obtain the formulation in claim 27-29 of the instant case with predictable results.
Claims 8-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of US’692 in view of JP’218.
Claim 1 and the teaching of US’692 regarding claim 1, are discussed above.
Claims 8-9 are drawn to the surfactant in claim 1 of the instant case to be a polyethylene such as PEG 3350.
US’692 does not claim a PEG surfactant.
However, JP’218 recites a stable liquid formulation with an organic co-solvent being polyethylene glycol 3350 (claim 8) at 0.085- 1.15% w/v (claim 9), which overlaps with the range of PEG in instant claims 1, 8 and 9, as discussed above.
Therefore, it would have been obvious for an ordinary artisan to utilize a polyethylene glycol such as PEG3350 as a co-solvent to replace the polysorbate in claim 1 of US’692 at a concentration of 0.01-0.19%w/v to obtain the formulation in claims 1, 8-9 of the instant case with reasonable expectation of success.
Claims 30, 36, 38 and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of US’692 in view of Grapentin et al. (2020), and in further view of BAK et al. (2019).
Instant claim 1 and the teaching of US’692 and Grapentin et al regarding claim 1 are discussed above.
US’692 does not teach a phospholipase protein or SVP in an antibody formulation.
The teaching of Bak et al regarding phospholipase B-like 2 protein (PLBL2) in an antibody formulation is discussed above (See 103 rejection).
The teaching of Grapentin et al regarding the amount of particles having a diameter of ≥10 mm and particles (≥25 mm) in the antibody formulation after storage for 6 months at 5°C is discussed above.
Based on the teaching of US’692, Grapentin et al and Bak et, it would have been obvious for a person with ordinary skills in the art to predict that after replacing the polysorbate in the antibody formulation in claim 1 of US’692 with poloxamer 188 at 0.01-0.19% w/v, the modified liquid pharmaceutical formulation would contain a phospholipase B-like 2 protein and that the formulation comprises no more than 150 particles having a diameter of >10 mm and no more than 50 particles having a diameter of ≥25 mm in a volume of 2.25 mL after storage for 6 months at 5°C, which meet the limitations in instant claims 30, 36, 38 and 40.
Instant claims 31, 33, 41, 43-55, 63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of US’692 in view of Grapentin et al. (2020), as applied to claims 44 and 47, and in further view of JP’218 as applied to claims 31, 33, 41, 43, 45-46, 49-54, and in further view of Hu et al US’845 (2020), as applied to claims 48, and 63.
Instant claim 1 and the teaching of US’692 and Grapentin et al regarding claim 1, are discussed above.
Instant claims 31, 33 and 41 are drawn to the stability of the liquid formulation upon agitation or exposure to high temperature at 45oC.
US’692 does not teach stability of the antibody formulation when subjected to agitation. Claim 7 of US’692 teach at least about 90% of the native form of the antibody in the formulation in claim 1 US’692 is recovered after about eight weeks of storage at about 45°C. US’692 does not explicitly teach stability when an antibody formulation is maintained at 45oC for a month.
The teaching of JP’218 regarding instant claims 31, 33 and 41 and the teaching of Grapentin et al (2020) regarding instant claim 41 are discussed above.
Based on the teachings of US’692, JP’218 and Grapentin et al, it would have been obvious for a person with ordinary skills in the art to modify the antibody formulation taught by US’692 by replacing polysorbate with poloxamer 188 at 0.01-0.19% w/v and predict the antibody formulation, after vortexing for up to 120 minutes at room temperature, to have HMW species (antibody aggregate) around 1.7%, which is lower than 3% recited in claim 31; and to have HMW species of about 5.1% after storage at 45° C for about 28 days, which is lower than 8% recited in claim 33, and to expect the level of the initial HMW % in the modified antibody formulation to be about 2% and the increase of % in HMW species to be within 0.3% after agitation for 24 hours since it is much shorter than 7 days tested by Grapentin et al, therefore the HMW species % would be around 2.3% after agitation of an antibody formulation for 24 hours at 25oC, which is lower than 4% recited in instant claim 41.
Instant claims 43-49 are drawn to the liquid formulation in claim 1 contained in various container or devices. Claim 1 of US’692 teach the prefilled syringe that reads to instant claims 44 and 47.
US’692 does not recites devices in instant claims 43, 45, 46 and 48-49.
However, JP’218 teach a similar IL-4R antibody formulation as discussed above, that is contained in a glass vial (claim 29), a microinfuser (claim 31) which is considered a large volume device or bolus injector; a syringe comprises a fluorocarbon coated plunger (claim 32), or a low tungsten syringe (claim 33).
Instant claims 50-53 are drawn to delivery devices or containers of the stable liquid formulation in claim 1. Claims 54 and 55 are considered duplicate claims of claim 53 as discussed above.
JP’218 teach the IL-4R antibody formulation described in claim 1 may be contained within any container suitable for the storage of medicaments and other therapeutic compositions (page 28, paragraph [0095]). JP’218 recites examples of reusable pen or autoinjector delivery devices as well as disposable pen or autoinjector delivery devices (page 30, paragraph [0099]).
Regarding instant claims 48, and 63, US’692 does not teach prefilled staked needle syringe. The teaching of Hu et al US’845 regarding these claims is discussed above.
Therefore, it would have been obvious for an ordinary artisan to use poloxamer 188 at 0.01-0.19% w/v in the formulation taught by US’692 and Grapentin et al and put it in the devices taught by JP’218 and Hu et al which read to those described in instant claims 43-49, 50-55 and 63 to serve different purpose of the modified formulation.
Instant claims 57-62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11, 12, 19-22 of US’692 in view of Grapentin et al (2020), and in further view of Dupixent, an FDA approved medicine (Dupixent label, Oct 2021)
Instant claims 57-62 are drawn to unit dosage forms of the liquid pharmaceutical formulation in claim 1.
Instant claim 1 and the teachings of US’692 and Grapentin et al (2020) regarding claim 1 are discussed above.
The teaching of FDA Dupixent label (Oct. 27, 2021) regarding the unit dosage of the active ingredient of Dupixent, Dupilumab, which reads on the antibody in claim 1 is discussed above.
Therefore, it would have been obvious for a person with ordinary skills in the art to replace the surfactant polysorbate 80 with poloxamer 188 at 0.01-0.19% w/v in Dupixent which reads to claim 1 of US’692, as taught by Grapentin et al and apply the same unit dosage forms taught by the FDA Dupixent label.
US Patent No. 10435473 (US’473)
Instant claims 1-31, 33, 36, 38, 40-41, 43-55, 57-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over US’473.
Instant claims 1-7, 10-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 17, 20-21 of US’473 in view of Grapentin et al (2020).
Regarding instant claims 1-26, claim 1 of US’473 recites: A stable pharmaceutical formulation comprising: (i) a human antibody at a concentration of from 15 mg/ml to 200 mg/ml, wherein the antibody specifically binds to human interleukin-4 receptor alpha (hIL-4Rα) and comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:5; (ii) acetate at a concentration of from 10 mM to 15 mM; (iii) histidine at a concentration of from 15 mM to 25 mM; (iv) sucrose at a concentration of from 2.5% w/v to 10% w/v; (v) polysorbate at a concentration of from 0.1% w/v to 0.3% w/v; and (vi) arginine at a concentration of from 20 mM to 100 mM, wherein the formulation has a pH of from 5.6 to 6.2.
The antibody in claim 1 US’473 bears identical HCVR/LCVR (SEQ ID No. 1/2) pairs (therefore contains identical HCDRs and LCDRs, SEQ ID No. 3, 4, 5 and SEQ ID No. 6, 7, 8) to the antibody in claims 2 and 3 of the instant application and are interpreted as full antibody that contains heavy chain constant region based on the specification of US’473.
Claims 1-8, 17, 20-21 of US’473 recite concentrations of antibody, buffers (acetate and histidine), thermal stabilizer (sucrose), viscosity modifier (arginine) and pH range of 5.6-6.2 that read to the corresponding components except the surfactant in instant claims 1-29, with identical or significant overlapping ranges.
US’473 does not recite a surfactant comprising a polyethylene glycol or a poloxamer at a concentration of 0.01-0.19% w/v.
However, Grapentin et al (2020) teach suitability and motivation of substituting polysorbate with poloxamer 188 in an antibody pharmaceutical formulation as discussed above.
According to MPEP2144.05, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. It is well within the abilities of an ordinary artisan to optimize the amount of antibody, sucrose, arginine, and pH in the formulation described in claim1 of US’473 and arrive at the concentrations claims 1-26 in the instant case through no more than routine experimentation.
Therefore, it would have been obvious for an ordinary artisan to substitute polysorbate in the stable pharmaceutical formulations in US’473 with poloxamer at a concentration of 0.01-0.19% w/v and adjust the concentration of other components and pH to arrive at the formulations in instant claims 1-29.
Instant claims 8-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of US’473 in view of JP’218.
Instant claim 1 and the teaching of US’473 regarding claim 1, are discussed above.
Instant claims 8-9 are drawn to the surfactant in claim 1 being a polyethylene such as PEG 3350.
US’473 does not claim a PEG surfactant.
However, JP’218 teaches an organic co-solvent being polyethylene glycol 3350 (claim 8) at 0.085- 1.15% w/v (claim 9) as discussed above.
Therefore, it would have been obvious for an ordinary artisan to utilize a polyethylene glycol such as PEG3350 as a co-solvent to replace the polysorbate in claim 1 of US’473 at a concentration of 0.01-0.19%w/v to obtain the formulation in claims 1, 8-9 of the instant case with reasonable expectation of success.
Claims 30, 36, 38 and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of US’473 in view of Grapentin et al. (2020), and in further view of BAK et al. (2019).
Instant claim 1 and the teaching of US’473 and Grapentin et al regarding claim 1 are discussed above.
US’473 does not teach a phospholipase protein or SVP in an antibody formulation.
Instant claims 30, 36, 38 and 40 and the teachings of BAK et al and Grapentin et al regarding these claims are discussed above.
Based on the teaching of US’473, Grapentin et al and Bak et al, it would have been obvious for a person with ordinary skills in the art to predict that after replacing the polysorbate in the antibody formulation in claim 1 of US’473 with poloxamer 188 at 0.01-0.19% w/v, the modified liquid pharmaceutical formulation would contain a phospholipase protein that is a phospholipase B-like 2 protein and that the formulation comprises no more than 150 particles having a diameter of >10 mm and no more than 50 particles having a diameter of ≥25 mm in a volume of 2.25 mL after storage for 6 months at 5°C, which meet the limitations in instant claims 30, 36, 38 and 40.
Instant claims 31, 33, 41, 43-55 and 63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12-16 of US’473 in view of Grapentin et al. (2020), as applied to claims 43-46, and 49, and in further view of JP’218 as applied to claims 31, 33, 41, 47, 50-55, and in further view of Hu et al US’845 (2020), as applied to claims 48, and 63.
Instant claim 1 and the teaching of US’473 and Grapentin et al regarding claim 1, are discussed above.
Instant claims 31, 33 and 41 are drawn to the stability of the liquid formulation in claim 1 upon agitation or exposure to high temperature at 45oC.
US’473 does not recite stability of the antibody formulation when subjected to agitation. Claims 11 and 19 of US’473 recite at least about 90% of the native form of the antibody in the formulations is recovered after about eight weeks of storage at about 45°C. US’473 does not explicitly teach stability when an antibody formulation is maintained at 45oC for a month.
The teaching of JP’218 regarding instant claims 31, 33 and 41 and the teaching of Grapentin et al (2020) regarding instant claim 41 are discussed above.
Based on the teachings of US’473, JP’218 and Grapentin et al, it would have been obvious for a person with ordinary skills in the art to modify the antibody formulation taught by US’473 by replacing polysorbate with poloxamer 188 at 0.01-0.19% w/v and predict the antibody formulation, after vortexing for up to 120 minutes at room temperature, to have HMW species (antibody aggregate) around 1.7%, which is lower than 3% recited in claim 31; and to have HMW species of about 5.1% after storage at 45° C for about 28 days, which is lower than 8% recited in claim 33, and to expect the level of the initial HMW % in the modified antibody formulation to be about 2% and the increase of % in HMW species to be within 0.3% after agitation for 24 hours since it is much shorter than 7 days tested by Grapentin et al, therefore the HMW species % would be around 2.3% after agitation of an antibody formulation for 24 hours at 25oC, which is lower than 4% recited in instant claim 41.
Instant claims 43-46 and 49 are drawn to the liquid formulation in claim 1 contained in various container or devices. Claims 12-16 of US’473 teach corresponding devices in instant claims 43-46 and 49, including a microinfusor which is considered a large volume device or bolus injector.
Regarding instant claims 47-48 and 63, US’473 does not recites a prefilled syringe or a prefilled staked syringe, or a safety system delivery device.
However, Hu et al US’845 teach prefilled staked needle syringe and safety system delivery device that are used to contain a similar antibody formulation, as discussed above.
Instant claims 50-55 and the teaching of JP’218 regarding these claims are discussed above.
Therefore, it would have been obvious for an ordinary artisan to use poloxamer 188 at 0.01-0.19% w/v in the formulation taught by US’473 and Grapentin et al and put it in the devices taught by JP’218 and Hu et al which read to those described in instant claims 43-49, 50-55 and 63 to serve different purpose of the modified formulation.
Instant claims 57-62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 17, 20-21 of US’473 in view of Grapentin et al (2020), and in further view of Dupixent, an FDA approved medicine (Dupixent label, Oct 2021)
Instant claims 57-62 are drawn to unit dosage forms of the liquid pharmaceutical formulation in claim 1.
Instant claim 1 and the teachings of US’473 and Grapentin et al (2020) regarding claim 1 are discussed above.
US’473 or Grapentin et al do not teach unit dosage of the liquid pharmaceutical formulation in claim 1.
However, the FDA Dupixent label (Oct. 27, 2021) teaches the unit dosages of Dupilumab, which meet the limitations in instant claims 57-62, as discussed above.
Therefore, it would have been obvious for a person with ordinary skills in the art to obtain a formulation in instant claim 1 as discussed above and apply the same unit dosage forms taught by the FDA Dupixent label.
US Patent No. 11059896 (US’896)
Instant claims 1-31, 33, 36, 38, 40-41, 43-55, 57-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over US’896.
Instant claims 1-7, 10-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11, 19-20, 22-23, 25-35, 42-45 of US’896 in view of Grapentin et al (2020).
Regarding instant claims 1-26, claim 1 of US’896 recites: A pen delivery device containing a stable liquid pharmaceutical formulation comprising: (i) a human antibody at a concentration of from 15 mg/ml to 200 mg/ml, wherein the antibody specifically binds to human interleukin-4 receptor alpha (hIL-4Rα) and comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:5; (ii) acetate at a concentration of from 10 mM to 15 mM; (iii) histidine at a concentration of from 15 mM to 25 mM; (iv) sucrose at a concentration of from 2.5% w/v to 10% w/v; (v) polysorbate at a concentration of from 0.1% w/v to 0.3% w/v; and (vi) arginine at a concentration of from 20 mM to 100 mM; wherein the formulation has a pH of from 5.6 to 6.2.
Claim 25 of US’896 recites an autoinjector device containing an identical formulation as in claim 1 of US’896.
The antibody in claims 1 and 25 of US’896 bears identical HCVR/LCVR (SEQ ID No. 1/2) pairs (therefore contains identical HCDRs and LCDRs, SEQ ID No. 3, 4, 5 and SEQ ID No. 6, 7, 8) to the antibody in claims 2 and 3 of the instant application and are interpreted as full antibody that contains heavy chain constant region based on the specification of US’896.
Claims 1-11, 25-35 of US’896 recite concentrations of antibody, buffers (acetate and histidine), thermal stabilizer (sucrose), viscosity modifier (arginine) and pH range of 5.6-6.2 that read to the corresponding components except the surfactant in instant claims 1-26, with identical or significant overlapping ranges.
Claims 19-20, 22-23, 42-45 of US’896 reads to the narrow concentration range of the antibody, excipients and pH, except the surfactant in instant claims 27-29.
US’896 does not recite a surfactant comprising a polyethylene glycol or a poloxamer at a concentration of 0.01-0.19% w/v.
However, Grapentin et al (2020) teach suitability and motivation of substituting polysorbate with poloxamer 188 in an antibody pharmaceutical formulation as discussed above.
According to MPEP2144.05, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. It is well within the abilities of an ordinary artisan to optimize the amount of antibody, sucrose, arginine, and pH in the formulation described in US’896 and arrive at the formulations of instant claims 1-29 in the instant case through no more than routine experimentation.
Therefore, it would have been obvious for an ordinary artisan to substitute polysorbate in the stable pharmaceutical formulations in US’896 with poloxamer at a concentration of 0.01-0.19% w/v and adjust the concentration of other components and pH to arrive at the formulation in claims 1-29 of the instant case.
Instant claims 8-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 25 of US’896 in view of JP’218.
Instant claim 1 and the teaching of US’896 regarding claim 1, are discussed above.
Instant claims 8-9 are drawn to the surfactant in claim 1 being a polyethylene such as PEG 3350.
US’896 does not claim a PEG surfactant.
However, JP’218 teaches an organic co-solvent being polyethylene glycol 3350 (claim 8) at 0.085- 1.15% w/v (claim 9) as discussed above.
Therefore, it would have been obvious for an ordinary artisan to utilize a polyethylene glycol such as PEG3350 as a co-solvent to replace the polysorbate in claims 1 and 25 of US’896 at a concentration of 0.01-0.19%w/v to obtain the formulation in claims 1, 8-9 of the instant case with reasonable expectation of success.
Claims 30, 36, 38 and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of US’896 in view of Grapentin et al. (2020), and in further view of BAK et al. (2019).
Instant claim 1 and the teaching of US’896 and Grapentin et al regarding claim 1 are discussed above.
Claims 30, 36, 38 and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 25 of US’896 in view of Grapentin et al. (2020), and in further view of BAK et al. (2019).
Instant claim 1 and the teaching of US’896 and Grapentin et al regarding claim 1 are discussed above.
US’896 does not teach a phospholipase protein or SVP in an antibody formulation.
Instant claims 30, 36, 38 and 40 and the teachings of BAK et al and Grapentin et al regarding these claims are discussed above.
Based on the teaching of US’896, Grapentin et al and Bak et al, it would have been obvious for a person with ordinary skills in the art to predict that after replacing the polysorbate in the antibody formulation in claim 1 of US’896 with poloxamer 188 at 0.01-0.19% w/v, the modified liquid pharmaceutical formulation would contain a phospholipase protein that is a phospholipase B-like 2 protein and that the formulation comprises no more than 150 particles having a diameter of >10 mm and no more than 50 particles having a diameter of ≥25 mm in a volume of 2.25 mL after storage for 6 months at 5°C, which meet the limitations in instant claims 30, 36, 38 and 40.
Instant claims 31, 33, 41, 43-55 and 63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of US’896 in view of Grapentin et al. (2020), as applied to claims 44 and 47, and in further view of JP’218 as applied to claims 31, 33, 41, 43, 45-46, 49-54, and in further view of Hu et al US’845 (2020), as applied to claims 48, and 63.
Instant claim 1 and the teaching of US’896 and Grapentin et al regarding claim 1, are discussed above.
Instant claims 31, 33 and 41 are drawn to the stability of the liquid formulation in claim 1 upon agitation or exposure to high temperature at 45oC.
US’896 does not recite stability of the antibody formulation when subjected to agitation. Claims 15 and 39 of US’896 recite at least about 90% of the native form of the antibody in the formulations is recovered after about eight weeks of storage at about 45°C. US’896 does not explicitly teach stability when an antibody formulation is maintained at 45oC for a month.
The teaching of JP’218 regarding instant claims 31, 33 and 41 and the teaching of Grapentin et al (2020) regarding instant claim 41 are discussed above.
Based on the teachings of US’896, JP’218 and Grapentin et al, it would have been obvious for a person with ordinary skills in the art to modify the antibody formulation taught by US’896 by replacing polysorbate with poloxamer 188 at 0.01-0.19% w/v and predict the antibody formulation, after vortexing for up to 120 minutes at room temperature, to have HMW species (antibody aggregate) around 1.7%, which is lower than 3% recited in claim 31; and to have HMW species of about 5.1% after storage at 45° C for about 28 days, which is lower than 8% recited in claim 33, and to expect the level of the initial HMW % in the modified antibody formulation to be about 2% and the increase of % in HMW species to be within 0.3% after agitation for 24 hours since it is much shorter than 7 days tested by Grapentin et al, therefore the HMW species % would be around 2.3% after agitation of an antibody formulation for 24 hours at 25oC, which is lower than 4% recited in instant claim 41.
Instant claims 43-49 are drawn to the liquid formulation in claim 1 contained in various container or devices.
US’896 does not recites these devices.
However, JP’218 teach a similar IL-4R antibody formulation as discussed above, that is contained in a glass vial (claim 28), a syringe (claim 29), a microinfuser (claim 30) which is considered a large volume device or bolus injector, a fluorocarbon coated plunger (claim 31) and a low tungsten syringe (claim 32).; a syringe comprises a fluorocarbon coated plunger (claim 32), or a low tungsten syringe (claim 33), which read to the devices recited in instant claims 43-46 and 49.
Instant claims 47, 48, and 63 and the teaching of Hu et al are discussed above.
Instant claims 50-55 are drawn to delivery devices or containers of the stable liquid formulation in claim 1 as discussed above.
Claims 1, 18 and 25 of US’896 recite a pen delivery device, a disposable pen delivery device and an autoinjector delivery device which contain a similar formulation, which read to these devices in instant claims 50 and 51
JP’218 recites examples of disposable pen or autoinjector delivery devices (page 30, paragraph [0099]).
Therefore, it would have been obvious for an ordinary artisan to use poloxamer 188 at 0.01-0.19% w/v in the formulation taught by US’896 and Grapentin et al and put it in the devices taught by US’896, JP’218 and Hu et al which read to those described in instant claims 43-49, 50-55 and 63 to serve different purpose of the modified formulation.
Instant claims 57-62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 25 of US’896 in view of Grapentin et al (2020), and in further view of Dupixent, an FDA approved medicine (Dupixent label, Oct 2021)
Instant claims 57-62 are drawn to unit dosage forms of the liquid pharmaceutical formulation in claim 1.
Instant claim 1 and the teachings of US’896 and Grapentin et al (2020) regarding claim 1 are discussed above.
US’896 or Grapentin et al do not teach unit dosage of the liquid pharmaceutical formulation in claim 1.
However, the FDA Dupixent label (Oct. 27, 2021) teaches the unit dosages of Dupilumab, which meet the limitations in instant claims 57-62, as discussed above.
Therefore, it would have been obvious for a person with ordinary skills in the art to obtain a formulation in instant claim 1 as discussed above and apply the same unit dosage forms taught by the FDA Dupixent label.
US Patent No. 11926670 (US’670)
Instant claims 1-31, 33, 36, 38, 40-41, 43-55, 57-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over US’670.
Instant claims 1-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13, 19-23 of US’670 in view of JP’218 and Grapentin et al (2020).
Regarding instant claims 1-29, claim 1 of US’670 recites: A pharmaceutical formulation comprising: (i) a human antibody at a concentration of about 100 mg/ml to about 200 mg/ml that specifically binds to human interleukin-4 receptor alpha (hIL-4Ra), wherein the antibody comprises (a) a heavy chain variable region (HCVR) comprising heavy chain complementarity determining regions 1, 2 and 3 (HCDR1-HCDR2-HCDR3) that comprise the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; and (b) a light chain variable region (LCVR) comprising light chain complementarity determining regions 1, 2 and 3 (LCDR1-LCDR2-LCDR3) that comprise the amino acid sequences of SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, respectively; (ii) acetate at a concentration of about 2.5 mM to about 22.5 mM; (iii) histidine at a concentration of about 10 mM to about 30 mM; (iv) an organic cosolvent that is a nonionic polymer containing a polyoxyethylene moiety at a concentration of from 0.2% w/v to 1% w/v; and (v) a sugar or a sugar alcohol at a concentration of about 2.5% w/v to about 10% w/v, wherein the formulation has a pH of from 5.6 to 6.2, and wherein at least about 92% of the antibody is in its native conformation after two weeks of storage at about 45° C., as determined by size exclusion chromatography. Claims 12 and 13 of US’670 recites the formulation in claim 1 US’670 further comprise arginine.
The antibody in claim1 of US’670 bears identical HCDRs and LCDRs, SEQ ID No. 3, 4, 5 and SEQ ID No. 6, 7, 8 that are contained in the HCVR/LCVR (SEQ ID No. 1/2) pairs (claim 2 of US’670) which are identical to those in the antibody in instant claims 2 and 3. The antibody is interpreted as full antibody that contains heavy chain constant region based on the specification of US’670.
Claims 1-13, 19-23 of US’670 recite concentrations of antibody, buffers (acetate and histidine), thermal stabilizer (sucrose), viscosity modifier (arginine) and pH range of 5.6-6.2 that read to the corresponding components except the surfactant in instant claims 1-29, with identical or significant overlapping ranges.
The co-solvent component of the formulation in these claims of US’670 reads to polyethylene glycol or poloxamer in the instant application, with the concentration range of the co-solvent at 0.2-1% w/v, which does not overlap with 0.01-0.19% w/v in instant claim 1.
However, JP’218 teach a stable liquid formulation with organic co-solvent selected from polysorbate, poloxamer or polyethylene glycol 3350 (claim 8) at about 0.085% to about 1.15% w/v (claim 9), which overlaps with the range of surfactant of polyethylene glycol or poloxamer at a concentration of 0.01-.019% w/v in claim 1 of the instant case.
According to MPEP2144.05, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. It is well within the abilities of an ordinary artisan to optimize the amount of antibody, sucrose, arginine, and pH in the formulation described in claims 1-13, 19-23 of US’670 and arrive at the corresponding concentrations in instant case through no more than routine experimentation.
Therefore, it would have been obvious for an ordinary artisan to utilize a polyethylene glycol such as PEG3350 at a concentration of 0.01-0.19%w/v taught by JP’218 and adjust the concentration of other excipients and pH in the formulation of claim 1 of US’670 to obtain the formulation in instant claims 1-29 with reasonable expectation of success.
Instant claims 57-62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1of US’670 in view of JP’218 and in further view of Dupixent, an FDA approved medicine (Dupixent label, Oct 2021).
Instant claims 57-62 are drawn to unit dosage forms of the liquid pharmaceutical formulation in claim 1.
Instant claim 1 and the teachings of US’670 and JP’218 regarding claim 1 are discussed above.
US’670 and JP’218 do not teach unit dosage of the liquid pharmaceutical formulation.
However, the FDA Dupixent label (Oct. 27, 2021) teaches the unit dosages of Dupilumab, which meet the limitations in instant claims 57-62, as discussed above.
Therefore, it would have been obvious for a person with ordinary skills in the art to modify the formulation in US’670 through no more than routine optimization, as taught by JP’218, to arrive at a formulation in instant claim 1, and apply the same unit dosage forms taught by the FDA Dupixent label.
Claims 30, 36, 38 and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 of US’670 in view of JP’218, and in further view of BAK et al (2019) and Grapentin et al (2020).
Instant claim 1 and the teaching of US’670 and JP’218 regarding claim 1 are discussed above.
US’670 and JP’218 do not teach a phospholipase protein or SVP in an antibody formulation.
Instant claims 30, 36, 38 and 40 and the teachings of BAK et al and Grapentin et al regarding these claims are discussed above.
Based on the teaching of US’670, JP’218, Bak et al and Grapentin et al, it would have been obvious for a person with ordinary skills in the art to predict that by modifying in the antibody formulation in claim 1 of US’670 with a PEG such as PEG3350 at 0.01-0.19% w/v, the modified liquid pharmaceutical formulation would contain a phospholipase protein that is a phospholipase B-like 2 protein and that the formulation comprises no more than 150 particles having a diameter of >10 mm and no more than 50 particles having a diameter of ≥25 mm in a volume of 2.25 mL after storage for 6 months at 5°C, which meet the limitations in instant claims 30, 36, 38 and 40.
Instant claims 31, 33, 41, 43-55 and 63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 14-18 of US’670 in view of JP’218 as applied to claims 31, 33, 43-46, 49 and 50-55, and in further view of Grapentin et al (2020) as applied to claim 41, and Hu et al (2020) as applied to claims 48 and 63.
Instant claim 1 and the teaching of US’670 and JP’218 et al regarding claim 1, are discussed above.
Instant claims 31, 33 and 41 are drawn to the stability of the liquid formulation in claim 1 upon agitation or exposure to high temperature at 45oC.
US’670 does not recite stability of the antibody formulation when subjected to agitation. Claim 1 of US’670 teach at least about 92% of the native form of the antibody in the formulations is recovered after about two weeks of storage at about 45°C. US’670 does not explicitly teach stability when an antibody formulation is maintained at 45oC for a month.
The teaching of JP’218 regarding instant claims 31, 33 and 41 and the teaching of Grapentin et al (2020) regarding instant claim 41 are discussed above.
Based on the teachings of US’670, JP’218 and Grapentin et al, it would have been obvious for a person with ordinary skills in the art to modify the antibody formulation taught by US’670 by using PEG3350 at 0.01-0.19% w/v and predict the antibody formulation, after vortexing for up to 120 minutes at room temperature, to have HMW species (antibody aggregate) around 1.7%, which is lower than 3% recited in claim 31; and to have HMW species of about 5.1% after storage at 45° C for about 28 days, which is lower than 8% recited in claim 33, and to expect the level of the initial HMW % in the modified antibody formulation to be about 2% and the increase of % in HMW species to be within 0.3% after agitation for 24 hours since it is much shorter than 7 days tested by Grapentin et al, therefore the HMW species % would be around 2.3% after agitation of an antibody formulation for 24 hours at 25oC, which is lower than 4% recited in instant claim 41.
Instant claims 43-46, 49 and 50-55 are drawn to the liquid formulation in claim 1 contained in various container or devices. Claims 14-18 of US’670 teach corresponding devices in instant claims 43, 44, 49 and 50, JP’218 teaches devices in instant claims 45, 46, 51-55 and Hu et al teaches devices in 47-48, as discussed above.
Therefore, it would have been obvious for an ordinary artisan to modify the formulation taught by US’670 and JP’218 to arrive at a formulation in instant claim 1, as discussed above, and put it in the devices taught by US’670, JP’218 and Hu et al to serve different purpose of the modified formulation.
US Application 18/432780 (App’780)
Instant claims 1-31, 33, 36, 38, 40-41, 43-55, 57-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 18/432780.
Instant claims 1-7, 10-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30-44, 46-59, 61-75, 76-90 of copending App’780 in view of Grapentin et al (2020).
Regarding instant claims 1-7, 10-29, claims 30, 46, 61 and 76 of App’780 recites A pharmaceutical formulation comprising: (i) an antibody or antigen-binding fragment thereof that specifically binds to human interleukin-4 receptor alpha (hIL-4Ra), wherein the antibody or antigen-binding fragment thereof is present at a concentration of about 15 mg/ml to about 200 mg/ml, and wherein the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region (HCVR) comprising heavy chain complementarity determining regions 1, 2, and 3 (HCDR1, HCDR2, and HCDR3) that comprise the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; and (b) a light chain variable region (LCVR) comprising light chain complementarity determining regions 1, 2, and 3 (LCDR1, LCDR2, and LCDR3) that comprise the amino acid sequences of SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, respectively; (ii) one or more buffers that can buffer from pH 5.6 to pH 6.2; (iii) a polysorbate at a concentration of from 0.2% w/v to 2% w/v; (iv) sucrose, mannitol, or trehalose at a concentration of about 2.5% w/v to about 10% w/v; and (v) arginine at a concentration of about 25 mM to about 100 mM; wherein the pharmaceutical formulation has a pH of from 5.6 to 6.2. Claims 46, 61, and 76 of App’780 recite a syringe, an autoinjector delivery device, or a pen delivery device comprising the same liquid formulation described in claim 30 App’780.
The antibody in claims 30, 46, 61, 76 in App’780 bears identical HCDRs/LCDRs pairs (SEQ ID No. 3, 4, 5/SEQ ID No. 6, 7, 8) that are contained in identical HCVR/LCVR (SEQ ID No. 1/2) pairs (claims 44, 60, 75, 90 of App’780) to the antibody in instant claims 2 and 3 and are interpreted as full antibody that contains heavy chain constant region based on the specification of App’780.
Claims 31-42, 47-59, 62-74, 77-89 of App’780 recite concentrations of antibody, buffers (acetate and histidine), thermal stabilizer (sucrose), viscosity modifier (arginine) and pH range of 5.6-6.2 that read to the corresponding components except the surfactant in instant claims 1-26, with identical or significant overlapping ranges.
App’780 does not recite a surfactant comprising a polyethylene glycol or a poloxamer at a concentration of 0.01-0.19% w/v.
However, Grapentin et al (2020) teach suitability and motivation of substituting polysorbate with poloxamer 188 in an antibody pharmaceutical formulation as discussed above.
According to MPEP2144.05, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. It is well within the abilities of an ordinary artisan to optimize the amount of antibody, sucrose, arginine, and pH in the formulation described in claims 30, 46, 61, 76 of App’780 and arrive at the concentrations of instant claims 1-29 through no more than routine experimentation.
Therefore, it would have been obvious for an ordinary artisan to substitute polysorbate in the stable pharmaceutical formulations in App’780 with poloxamer at a concentration of 0.01-0.19% w/v and adjust the concentration of other components and pH to arrive at the formulation in claims 1-7, 10-29 of the instant case.
Instant claims 8-9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30, 46, 61, 76 of copending App’780 in view of JP’218.
Instant claim 1 and the teaching of App’780 regarding claims 30, 46, 61, 76, are discussed above.
Instant claims 8-9 are drawn to the surfactant in claim 1 to be a polyethylene such as PEG 3350.
App’780 does not claim a PEG surfactant.
However, JP’218 teaches an organic co-solvent being polyethylene glycol 3350 (claim 8) at 0.085- 1.15% w/v (claim 9) as discussed above.
Therefore, it would have been obvious for an ordinary artisan to utilize a polyethylene glycol such as PEG3350 at a concentration of 0.01-0.19%w/v as a co-solvent to replace the polysorbate in the formulation in claims 30, 46, 61, 76 of App’780 to obtain the formulation in claims 1, 8-9 of the instant case with reasonable expectation of success.
Instant claims 57-62 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30, 46, 61, 76 of copending App’780 in view of Grapentin et al (2020) and in further view of Dupixent, an FDA approved medicine (Dupixent label, Oct 2021).
Instant claims 57-62 are drawn to unit dosage forms of the liquid pharmaceutical formulation in claim 1.
Instant claim 1 and the teachings of App’780 and Grapentin et al (2020) regarding claim 1 are discussed above.
App’780 or Grapentin et al do not teach unit dosage of the liquid pharmaceutical formulation.
However, the FDA Dupixent label (Oct. 27, 2021) teaches the unit dosages of Dupilumab, which meet the limitations in instant claims 57-62, as discussed above.
Therefore, it would have been obvious for a person with ordinary skills in the art to modify the formulation in App’780 through no more than routine optimization, as taught by Grapentin et al, to arrive at a formulation in instant claim 1, and apply the same unit dosage forms taught by the FDA Dupixent label.
Instant claims 30, 36, 38 and 40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30, 46, 61, 76 of copending App’780 in view of Grapentin et al. (2020), and in further view of BAK et al. (2019).
Instant claim 1 and the teaching of App’780 and Grapentin et al regarding claim 1 are discussed above.
App’780 and Grapentin et al do not teach a phospholipase protein or SVP in an antibody formulation.
Instant claims 30, 36, 38 and 40 and the teachings of BAK et al and Grapentin et al regarding these claims are discussed above.
Based on the teaching of App’780, Grapentin et al, and Bak et al, it would have been obvious for a person with ordinary skills in the art to predict that by modifying in the antibody formulation in claim 1 of App’780 as discussed above and arrive at a formulation in instant claim 1, the modified formulation would contain a phospholipase protein that is a phospholipase B-like 2 protein and that the formulation comprises no more than 150 particles having a diameter of >10 mm and no more than 50 particles having a diameter of ≥25 mm in a volume of 2.25 mL after storage for 6 months at 5°C, which meet the limitations in instant claims 30, 36, 38 and 40.
Instant claims 31, 33, 41, 43-55 and 63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30, 45, 46, 61 and 76 of copending App’780 in view of Grapentin et al. (2020), as applied to claims 43, 44, 49, and 50, and in further view of JP’218 as applied to claims 31, 33, 41, 45-46, 50-55, and Hu et al US’845 (2020), as applied to claims 47-48, and 63.
Instant claim 1 and the teaching of App’780 and Grapentin et al regarding claim 1, are discussed above.
Instant claims 31, 33 and 41 are drawn to the stability of the liquid formulation in claim 1 upon agitation or exposure to high temperature at 45oC.
App’780 does not recite stability of the antibody formulation when subjected to agitation or high temperature.
The teaching of JP’218 regarding instant claims 31, 33 and 41 and the teaching of Grapentin et al (2020) regarding instant claim 41 are discussed above.
Based on the teachings of App’780, JP’218 and Grapentin et al, it would have been obvious for a person with ordinary skills in the art to modify the antibody formulation taught by App’780 as discussed above and predict the modified antibody formulation, after vortexing for up to 120 minutes at room temperature, to have HMW species (antibody aggregate) around 1.7%, which is lower than 3% recited in claim 31; and to have HMW species of about 5.1% after storage at 45° C for about 28 days, which is lower than 8% recited in claim 33, and to expect the level of the initial HMW % in the modified antibody formulation to be about 2% and the increase of % in HMW species to be within 0.3% after agitation for 24 hours since it is much shorter than 7 days tested by Grapentin et al, therefore the HMW species % would be around 2.3% after agitation of an antibody formulation for 24 hours at 25oC, which is lower than 4% recited in instant claim 41.
Instant claims 43-49, 50-55 are drawn to the liquid formulation in claim 1 contained in various container or devices or devices containing the liquid formulation in claim1.
Regarding instant claims 43, 44, 49 and 50, claims 45, 46, 61, 76 of App’780 recites corresponding devices.
As discussed above, JP’218 teaches devices in instant claims 45, 46, 51-55. Hu et al teaches devices in 47-48.
Therefore, it would have been obvious for an ordinary artisan to use poloxamer 188 at 0.01-0.19% w/v in the formulation taught by App’780 and Grapentin et al and put it in the devices taught by JP’218 and Hu et al which read to those described in instant claims 43-49, 50-55 and 63 to serve different purpose of the modified formulation.
This is a provisional nonstatutory double patenting rejection.
Conclusion
All claims are rejected.
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/HONG REN/
Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647