Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election with traverse of the invention of Group I drawn to a method of obtaining a freeze-dried anti-α4β7 antibody formulation using a lyophilization method and species (a) in the reply filed on 04/16/2026 is acknowledged. The traversal is on the ground(s) that all pending share a single general inventive concept directed to the preparation and stabilization of an anti-α4β7 antibody formulation using defined excipients and lyophilization conditions. Applicant disagrees that the common technical feature specified in the restriction requirement –an anti-α4β7 antibody formulation –does not reflect the full set of shared technical features, only a subset. Further, Applicant argues that a specific search or examination burden has not been set forth. This argument is not found persuasive. A group of inventions is considered linked to form a single general inventive concept where there is a technical relationship among the inventions that involves at least one common or corresponding special technical feature. In the present case, the shared technical feature between the inventions of Groups I and II is the anti-α4β7 antibody formulation. This shared technical feature does not make a contribution over the prior art in view of Diluzio et al as discussed in the Restriction/Election Requirement of 02/05/2026. The product claims are directed to an anti-α4β7 antibody formulation that is not limited by, and need not be produced by, the claimed methods steps. Thus, the claimed lyophilization method can be used to produce a materially different anti-α4β7 antibody formulation having different concentration and types of buffers and other excipients. Therefore, the restriction requirement is deemed proper. However, in the interest of compact prosecution, the restriction requirement between the inventions of Groups I and II is withdrawn; and the product claim will be examined with the elected method species.
With regard to the species election, Applicant argues that the method species overlap in scope, differing only in the level of process detail or the inclusion of upstream purification steps. In particular, claim 1 is broad and claim 2 (previously an independent claim) is directed to additional process steps performed prior to the primary and secondary drying in the lyophilization method of claim 1. Further, Applicant argues that the election of species requires a generic claim, mutually exclusive species, and an articulated search burden. This argument is not found persuasive. The species election requirement is based on whether the claimed subject matter shares a technical feature that provides contribution over the prior art. In the present case, the claims encompass multiple process embodiments that differ in process step complexity, including the absence or presence of upstream purification steps. For example, lyophilization generally requires freezing, primary drying, and secondary drying. Annealing is an optional step applied after the freezing stage and is not a common feature in all lyophilization processes. Claim 2, previously as an independent claim, thus recited a different lyophilization method present in claim 1 that was further limited by specific stepwise increase in shelf temperature during the primary drying phase and antibody formulation. Claim 11 requires upstream antibody expression and ultrafiltration steps for a generic anti-α4β7 antibody formulation and lyophilization process. These differences represent distinct technical features and are not unified by a common special technical feature and thus require a separate search and examination. The shared feature of an anti-α4β7 antibody formulation while common to all claims does not constitute as a special technical feature that makes a contribution over the prior art. Thus, the species election requirement is deemed proper and maintained. However, it is noted that claim 2 has been amended to depend from claim 1. As such, claims identified under method species (b) (claims 2 and 12-16) are also examined in the present Office Action. Lastly, in response to Applicant’s concerns regarding responsive species election, the Examiner acknowledges that a proper species election was made.
Claims 1 -10 and 12-16 are examined on the merits in the present Office Action.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 2, 9, and 12-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for specific anti-α4β7 antibody formulations having an empirically determined glass transition temperature of -28℃, does not reasonably provide enablement for the full scope of generic anti-α4β7 antibody formulations defined as having glass transition temperature of -28℃ since the glass transition temperature can vary depending on the specific formulation. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
The nature of the invention relates to a process of making room-temperature stable reconstituted freeze-dried integrin antibody formulations (see Field of Invention).
Claim 2 (which depends on claim 1) recites that the primary drying of a generic anti-α4β7 antibody composition comprising a sugar, amino acid, and surfactant, is conducted in a stepwise approach, wherein the first temperature in the stepwise approach is carried out at the glass transition (Tg) temperature of the composition, specified as -28℃. Thus, claim 2 assigns a specific glass transition temperature (-28℃) to generic antibody formulations.
The specification teaches the preparation of several vedolizumab (an anti-α4β7 antibody) formulations for lyophilization (see Example 1 and Table 1). Prior to lyophilization, the glass transition temperature of the various formulations was purportedly measured using differential scanning calorimetry (DSC) and the same glass transition temperature (Tg) values were selected as the first temperature of primary drying, which was conducted in a stepwise approach with increasing shelf temperatures (see Table 2: Lyophilization Cycle for vedolizumab lyophilized product). However, the specification does not demonstrate that all anti-α4β7 antibody compositions encompassed by claim 2 possess a glass transition temperature of -28℃, nor does it provide guidance sufficient to achieve such a condition without under experimentation.
The prior art teaches that the glass transition temperature of a freeze-concentrated solution (Tg’) is dependent on the specific factors of a pharmaceutical formulation, including the concentration and type of the solutes, buffer composition, pH and ionic strength (Hauptmann et al, 4th paragraph of Introduction). For example, dehydrated lactose mixed with 10% (molar fraction) NaCl or KCl was reported to have a slightly lower Tg than pure lactose. Similarly, the addition of tris buffer to sucrose or trehalose caused a gradual decrease in the Tg of the sugar/tris buffer mixture with increasing concentration (Weng et al, 2nd paragraph of Introduction). The ratio of non-reducing sugar to protein (mole:mole) and the amounts of other formulation components will impact the glass transition temperature and collapse temperature (Diluzio et al, Para. 0146). Rather, the glass transition temperature for a given formulation must be determined empirically. Since the glass transition temperature Tg’ helps guide the lyophilization process, a mismatch between a an anti-α4β7 antibody formulation encompassed by the claim and the specified Tg of -28℃, can negatively impact product stability and quality (see HTD Biosystems: Lyophilization Cycle Optimization, particularly, “Primary Glass Transition Temperature” section). Claims 9 and 12-16, which depend on claim 2, do not cure the deficiencies of claim 2, and thus are also rejected.
While claim 12 (which depends on claim 2) recites specific types of excipients (e.g. trehalose, arginine, NaCl, phosphate-histidine buffer, polysorbate) present in the formulation, the concentration of some of these excipients is not particularly limited. The use of “at least” renders the claimed concentrations non-limiting thereby permitting an unlimited number of distinct formulations encompassed by the claim scope. For example, formulations comprising “at least 70 mg/mL” trehalose encompassing compositions at 70 mg/mL, 100 mg/mL, 200 mg/mL and so on without limitation. As discussed, variations in even the concentration of an excipient such as the ratio of a non-reducing sugar to protein (mole:mole) can lead to unpredictable changes in the glass transition temperature.
A person of ordinary skill in the art at the time of filing would have had experience in antibody formulations and freeze-drying techniques. Even at this high level of skill, however, determination of the glass transition temperature cannot be readily predicted for a generic antibody formulation without additional testing. Further, artisans would have to engage in additional experimentation to determine an optimal anti-α4β7 antibody formulation having the exact glass transition temperature of -28℃ specified in the claims. Thus, the level of skill does not obviate the need for substantial experimentation across the full scope of the claimed genus.
Therefore, the specification is not enabled over the full scope of the claims.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-7, 9, 12-16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites a lyophilization method comprising the steps of primary drying and secondary drying, wherein primary drying is carried out at different temperatures including at “a first temperature which is at the glass transition temperature of the antibody composition and holding it at the glass transition temperature”. In the context of lyophilization processes, a person of ordinary skill in the art would recognize that “glass transition temperature” can refer to the glass transition temperature of the dried amorphous formulation (Tg) or the glass transition temperature of the freeze-concentrated matrix in the frozen state (Tg’), which are distinct physical parameters (see Pansare et al, Abstract). Claims 3-7 depend on claim 1 but do not cure the deficiencies of claim 1 and are thus also rejected.
Claim 2 (which depends on claim 1) recites the limitation "a lyophilization method" in line 2. There is insufficient antecedent basis for this limitation in the claim. The phrase “lyophilization method” is first introduced in claim 1 and is preceded by an indefinite article (i.e. “a”); thus, any subsequent reference to this phrase in a dependent claim should be preceded with a definite article (e.g. “said” or “the”). As presently written, claim 2 still reads as a separate, standalone method even though it was amended to be dependent on claim 1.
Claim 2 recites a lyophilization method comprising the steps of
preparing a liquid anti-α4β7 antibody composition
freezing the liquid antibody composition at a temperature, ranging from about -45℃ to about -50℃,
annealing the frozen antibody composition at a temperature, ranging from about -22℃ to about -25℃,
refreezing the antibody composition at a temperature, ranging from about -45℃ to about -50℃,
primary drying of the antibody composition in a stepwise approach subjecting to different temperatures ranging from about -25℃ to about 0℃, and
secondary drying of the primary dried antibody composition at a temperature ranging from about 10℃ to about 25℃.
The lyophilization cycle presented in Example 1 of the specification appear to describe holding temperatures at distinct setpoints (e.g. -45℃ for freezing and refreezing, -22℃ for annealing, 25℃ for secondary drying), suggesting operation at set temperatures rather than across a range. However, as presently written, it is unclear the recited process steps highlighted above are intended to be performed across the claimed ranges or at single temperature selected within each recited range. Additionally, the term “about” is a relative term which renders the claim indefinite. The term is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. As such, the metes and bounds of the claimed temperature ranges cannot be determined with certainty.
Further, claim 2 recites that the primary drying phase is carried out stepwise at different temperatures between “about -25℃ to about 0℃”; however, immediately thereafter the claim recites the first temperature in the stepwise approach is -28℃, which is outside the lower limit of the recited temperature range. As stated earlier, the term “about” is not defined in the specification, and therefore, the metes and bounds of the recited temperature range for the primary drying phase cannot be determined with reasonable certainty. As a result, it is unclear whether temperatures the “first temperature” of -28℃ falls within the scope of the stepwise approach. Thus, the claim presents conflicting temperature limitations that renders the claim scope indefinite.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2, 9, and 12-16 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 2 has been amended to depend on claim 1 but fails to further limit the subject matter of the claim from which it depends. In particular, claim 2 recites “a lyophilization method comprising” a series of steps including freezing, annealing, refreezing, primary drying, and secondary drying. First, because claim 2 recites “a lyophilization method” and “comprising” rather than “the lyophilization method” and “further comprising”, the claim does not properly anchor itself to the independent claim. As a result, the claim appears to introduce a new lyophilization method having more process steps and thus improperly broadens, rather than further limits, the scope of independent claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-10 and 12-16 are rejected under 35 U.S.C. 103 as being unpatentable over Jayaraman et al (WO2019198100A1), hereinafter Jayaraman in view of Diluzio et al (US20140377251A1), hereinafter Diluzio, Velaradi et al (US8800162B2), hereinafter Velaradi, and Meyvis et al (US20160090424A1), hereinafter Meyvis.
Jayaraman discloses stable liquid formulations of an anti-α4β7 antibody comprising a buffer, sugar, free amino acid, salt, and surfactant. In a specific example, the formulation comprises 60 mg/mL of the anti-α4β7 antibody vedolizumab, 20 - or 40-mM phosphate-histidine buffer, 70 mg/mL trehalose, 5.3 mg/mL arginine-HCl, 2.92 mg/mL NaCl, 0.6 mg/mL polysorbate 80, and 1 mg/mL glycine at pH 6.0 (see Table 13 of Example 6, in particular, Vmab-16 and Vmab-18 formulations). The stable liquid formulations disclosed can be lyophilized, and the lyophilized formulation of the anti-α4β7 antibody can be reconstituted with appropriate diluent to achieve the liquid formulation suitable for administration (Page 9, Ln. 3-6).
Jayaraman does not specifically disclose the lyophilization process recited in the claims used to obtain a freeze-dried powder of the anti-α4β7 antibody formulation.
However, Diluzio discloses a method of preparing a stable, freeze-dried anti-α4β7 antibody formulation via a lyophilization process involving three main steps: freezing, primary drying, and secondary drying (Para. 0144). In general, the formulation is frozen at a temperature of about −30° C. or less such as −40° C. or −50° C) (Para. 0146). Once the formulation is frozen, the atmospheric pressure is reduced and the temperature is adjusted to allow removal of the frozen solvent through sublimation during primary drying (Para. 0144). Primary drying temperatures are selected as approximately 10-50℃ above freezing temperatures, which results in primary drying temperatures that can fall within approximately -30℃ to 0℃ (Para. 0146). The temperature is then raised to remove any solvent that is still bound to the dry formulation by evaporation during secondary drying, which is conducted at a temperature that is above the freezing temperature of the liquid formulation such as about 10° to about 50° C. In one particular embodiment, the temperature for secondary drying is ambient temperature, e.g., 20-30° C. The time for secondary drying should be sufficient to reduce the amount of moisture to <5% (Para. 0144 and Para. 0151). An optional step after freezing and before primary drying is annealing, wherein the shelf temperature is raised above the glass transition temperature of the formulation for a short period of time then lowered again to below the glass transition temperature of the formulation. An annealing step of an anti-α4β7 antibody formulation can be at about −30° C. to about −10° C. or about −25° C. to about −15° C. In one particular embodiment, an annealing temperature for an α4β7 antibody formulation is about −20° C (Para. 0150). An exemplary lyophilization cycle includes freezing at about −45° C, annealing at about −20° C, refreezing at about −45° C, primary drying at about −24° C and 150 mTorr, and secondary drying at about 27° C and 150 mTorr (Para. 0152). Lyophilized vials of anti-α4β7 antibody are stored at −70° C., −20° C., 2-8° C. or 25° C. for desired periods of time (Para. 0203). The anti-α4β7 antibody formulations can have ≦1.0% aggregate or ≦0.5% aggregate (Para. 0112). Acceptable quality levels an anti-α4β7 antibody dry, solid formulation include ≦2.5% moisture content, ≦20 minutes reconstitution time, and ≦ 2.5% of aggregates (Para. 0101, 0110, and 0195).
Velaradi further teaches that the primary drying phase of a freeze-drying cycle can be optimized by calculating and applying a sequence of shelf temperatures up to the end of the primary drying phase in order to maximize a sublimation rate of the product and maintain the product temperature below a maximum allowable product temperature (Abstract). In other words, adjusting the shelf temperature through a sequence of heating steps reduces the duration or primary drying while maintaining the product at a safe temperature level (Col. 4, Ln. 65-67). Thus, primary drying can be conducted using a sequence of shelf-temperatures rather than at constant shelf temperature.
Meyvis further illustrates a lyophilization process in which the primary drying phase is conducted using multiple shelf temperatures. After freezing, shelf temperature was gradually increased from -50℃ to -20℃ to 5℃ during primary drying. Each temperature is held constant for a defined period of time before transitioning to the next step, demonstrating that primary drying can consist of a stepwise increase of shelf temperatures with multiple hold periods (see Table 14: Lyophilization Parameters).
Therefore, it would have been obvious to one of ordinary skill in the art to apply the lyophilization method of Diluzio to prepare a freeze-dried powder of the anti-α4β7 antibody formulations disclosed by Jayaraman, wherein the primary drying phase is further optimized to comprise a sequence of shelf temperatures rather than a constant set point. One of ordinary skill in the art would have been motivated to do so since the lyophilization process steps described by Diluzio –freezing, annealing, refreezing, primary drying, and secondary drying—can be used to prepare a stable, freeze-dried anti-α4β7 antibody formulation such as one having ≦2.5% moisture content, a reconstitution time of ≦20 minutes, and ≦2.5% aggregates. Further, the primary drying phase of the freeze-drying cycle can be optimized by applying a sequence of shelf temperatures up to the end of the primary drying phase in order to reduce the duration of the primary drying phase while maintain the product integrity as taught by Velaradi. Meyvis in particular exemplifies a primary drying phase consisting of a stepwise increase of shelf temperatures with multiple hold periods. Accordingly, the primary drying phase can be conducted using a sequence of increasing shelf-temperatures rather than a single constant shelf temperature. Shelf temperatures and chamber pressures during each lyophilization step—including freezing, annealing, refreezing, primary drying, and secondary drying—are recognized in the prior art as results-effective variables. The courts have stated that "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimal lyophilization parameters including shelf temperatures and chamber pressures of each step, thereby arriving at the specific embodiments of the instant claims, including a stepwise primary drying phase initiated at the glass transition temperature of the anti-α4β7 antibody formulation. Moreover, the “wherein clauses” reciting expected stability of the lyophilized or reconstituted formulation in claims 1, 2, 5-7, and 1-15 are statements of intended result and, as such, do not impart patentable weight. Therefore, one of ordinary skill in the art would reasonably expect that a stable, freeze-dried anti-α4β7 antibody formulation of Jayaraman can be prepared using the lyophilization method disclosed by Diluzio, wherein the primary drying phase is further modified to comprise a sequence of shelf temperatures rather as taught by Velaradi and exemplified by Meyvis.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 and 4-7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. US12433947B2 in view of Diluzio et al (US20140377251A1), hereinafter Diluzio, Velaradi et al (US8800162B2), hereinafter Velaradi, and Meyvis et al (US20160090424A1), hereinafter Meyvis.
The issued claims recite a stable pharmaceutical formulation of comprising 60 mg/ml of 20 mM of phosphate buffer, 60 mg/ml of sucrose or trehalose, a surfactant at a pH of 6.0 to 7.0, wherein the formulation is devoid of free amino acid and is devoid of salt of amino acid, and wherein the amount of aggregate and fragment content is less than about 2% and less than about 1.5% respectively, when stored at 50° C. for two weeks (issued claims 1 and 2). Further recited is a method of making the stable pharmaceutical formulation of vedolizumab (issued claims 3 and 4).
The issued claims do not specifically recite that the method of making the stable formulation of the anti-α4β7 antibody is a lyophilization process.
However, Diluzio discloses a method of preparing a stable, freeze-dried anti-α4β7 antibody formulation via a lyophilization process involving three main steps: freezing, primary drying, and secondary drying (Para. 0144). In general, the formulation is frozen at a temperature of about −30° C. or less such as −40° C. or −50° C) (Para. 0146). Once the formulation is frozen, the atmospheric pressure is reduced and the temperature is adjusted to allow removal of the frozen solvent through sublimation during primary drying (Para. 0144). Primary drying temperatures are selected as approximately 10-50℃ above freezing temperatures, which results in primary drying temperatures that can fall within approximately -30℃ to 0℃ (Para. 0146). The temperature is then raised to remove any solvent that is still bound to the dry formulation by evaporation during secondary drying, which is conducted at a temperature that is above the freezing temperature of the liquid formulation such as about 10° to about 50° C. In one particular embodiment, the temperature for secondary drying is ambient temperature, e.g., 20-30° C. The time for secondary drying should be sufficient to reduce the amount of moisture to <5% (Para. 0144 and Para. 0151). An optional step after freezing and before primary drying is annealing, wherein the shelf temperature is raised above the glass transition temperature of the formulation for a short period of time then lowered again to below the glass transition temperature of the formulation. An annealing step of an anti-α4β7 antibody formulation can be at about −30° C. to about −10° C. or about −25° C. to about −15° C. In one particular embodiment, an annealing temperature for an α4β7 antibody formulation is about −20° C (Para. 0150). An exemplary lyophilization cycle includes freezing at about −45° C, annealing at about −20° C, refreezing at about −45° C, primary drying at about −24° C and 150 mTorr, and secondary drying at about 27° C and 150 mTorr (Para. 0152). Lyophilized vials of anti-α4β7 antibody are stored at −70° C., −20° C., 2-8° C. or 25° C. for desired periods of time (Para. 0203). The anti-α4β7 antibody formulations can have ≦1.0% aggregate or ≦0.5% aggregate (Para. 0112). Acceptable quality levels an anti-α4β7 antibody dry, solid formulation include ≦2.5% moisture content, ≦20 minutes reconstitution time, and ≦ 2.5% of aggregates (Para. 0101, 0110, and 0195).
Velaradi further teaches that the primary drying phase of a freeze-drying cycle can be optimized by calculating and applying a sequence of shelf temperatures up to the end of the primary drying phase in order to maximize a sublimation rate of the product and maintain the product temperature below a maximum allowable product temperature (Abstract). In other words, adjusting the shelf temperature through a sequence of heating steps reduces the duration or primary drying while maintaining the product at a safe temperature level (Col. 4, Ln. 65-67). Thus, primary drying can be conducted using a sequence of shelf-temperatures rather than at constant shelf temperature.
Meyvis further illustrates a lyophilization process in which the primary drying phase is conducted using multiple shelf temperatures. After freezing, shelf temperature was gradually increased from -50℃ to -20℃ to 5℃ during primary drying. Each temperature is held constant for a defined period of time before transitioning to the next step, demonstrating that primary drying can consist of a stepwise increase of shelf temperatures with multiple hold periods (see Table 14: Lyophilization Parameters).
Therefore, it would have been obvious to one of ordinary skill in the art to apply the lyophilization method of Diluzio to prepare a freeze-dried powder of the anti-α4β7 antibody formulations recited by the issued claims, wherein the primary drying phase is further optimized to comprise a sequence of shelf temperatures rather than a constant set point as taught by Velradi. One of ordinary skill in the art would have been motivated to do so since the lyophilization process steps described by Diluzio –freezing, annealing, refreezing, primary drying, and secondary drying—can be used to prepare a stable, freeze-dried anti-α4β7 antibody formulation such as one having ≤2.5% moisture content, a reconstitution time of ≤20 minutes, and ≤ 2.5% of aggregates. Further, the primary drying phase of the freeze-drying cycle can be optimized by applying a sequence of shelf temperatures up to the end of the primary drying phase in order to reduce the duration of the primary drying phase while maintain the product integrity as taught by Velaradi. Meyvis in particular exemplifies a primary drying phase consisting of a stepwise increase of shelf temperatures with multiple hold periods. Accordingly, the primary drying phase can be conducted using a sequence of increasing shelf-temperatures rather than a single constant shelf temperature. Shelf temperatures and chamber pressures during each lyophilization step—including freezing, annealing, refreezing, primary drying, and secondary drying—are recognized in the prior art as results-effective variables. The courts have stated that "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimal lyophilization parameters including shelf temperatures and chamber pressures of each step, thereby arriving at the specific embodiments of the instant claims, including a stepwise primary drying phase initiated at the glass transition temperature of the anti-α4β7 antibody formulation. Moreover, the “wherein clauses” reciting expected stability of the lyophilized or reconstituted formulation in claims 1, 2, 5-7, and 1-15 are statements of intended result and, as such, do not impart patentable weight. Therefore, one of ordinary skill in the art would reasonably expect that a stable, freeze-dried anti-α4β7 antibody formulation of the issued claims can be prepared using the lyophilization method disclosed by Diluzio, wherein the primary drying phase is further modified to comprise a sequence of shelf temperatures rather as taught by Velaradi and exemplified by Meyvis.
Claims 1-10 and 12-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 12030948B2 in view of Diluzio et al (US20140377251A1), hereinafter Diluzio, Velaradi et al (US8800162B2), hereinafter Velaradi, and Meyvis et al (US20160090424A1), hereinafter Meyvis.
The issued claims recite a pharmaceutical formulation comprising 50-200 mg/mL of the anti-α4β7 antibody vedolizumab; <80 mg/mL trehalose, histidine-phosphate buffer at pH of 6.0 to 7.0; < 15 mg/mL of a free amino acid selected from arginine, lysine, or glycine; salt; and surfactant, wherein the formulation is stable at 40° C. for two weeks and maintains at least 95% of the monomeric content of the antibody under above mentioned storage conditions (issued claims 1-6).
The issued claims do not recite a method of making a freeze-dried powder of the anti-α4β7 antibody formulation via a lyophilization process.
However, Diluzio discloses a method of preparing a stable, freeze-dried anti-α4β7 antibody formulation via a lyophilization process involving three main steps: freezing, primary drying, and secondary drying (Para. 0144). In general, the formulation is frozen at a temperature of about −30° C. or less such as −40° C. or −50° C) (Para. 0146). Once the formulation is frozen, the atmospheric pressure is reduced and the temperature is adjusted to allow removal of the frozen solvent through sublimation during primary drying (Para. 0144). Primary drying temperatures are selected as approximately 10-50℃ above freezing temperatures, which results in primary drying temperatures that can fall within approximately -30℃ to 0℃ (Para. 0146). The temperature is then raised to remove any solvent that is still bound to the dry formulation by evaporation during secondary drying, which is conducted at a temperature that is above the freezing temperature of the liquid formulation such as about 10° to about 50° C. In one particular embodiment, the temperature for secondary drying is ambient temperature, e.g., 20-30° C. The time for secondary drying should be sufficient to reduce the amount of moisture to <5% (Para. 0144 and Para. 0151). An optional step after freezing and before primary drying is annealing, wherein the shelf temperature is raised above the glass transition temperature of the formulation for a short period of time then lowered again to below the glass transition temperature of the formulation. An annealing step of an anti-α4β7 antibody formulation can be at about −30° C. to about −10° C. or about −25° C. to about −15° C. In one particular embodiment, an annealing temperature for an α4β7 antibody formulation is about −20° C (Para. 0150). An exemplary lyophilization cycle includes freezing at about −45° C, annealing at about −20° C, refreezing at about −45° C, primary drying at about −24° C and 150 mTorr, and secondary drying at about 27° C and 150 mTorr (Para. 0152). Lyophilized vials of anti-α4β7 antibody are stored at −70° C., −20° C., 2-8° C. or 25° C. for desired periods of time (Para. 0203). The anti-α4β7 antibody formulations can have ≦1.0% aggregate or ≦0.5% aggregate (Para. 0112). Acceptable quality levels an anti-α4β7 antibody dry, solid formulation include ≦2.5% moisture content, ≦20 minutes reconstitution time, and ≦ 2.5% of aggregates (Para. 0101, 0110, and 0195).
Velaradi further teaches that the primary drying phase of a freeze-drying cycle can be optimized by calculating and applying a sequence of shelf temperatures up to the end of the primary drying phase in order to maximize a sublimation rate of the product and maintain the product temperature below a maximum allowable product temperature (Abstract). In other words, adjusting the shelf temperature through a sequence of heating steps reduces the duration or primary drying while maintaining the product at a safe temperature level (Col. 4, Ln. 65-67). Thus, primary drying can be conducted using a sequence of shelf-temperatures rather than at constant shelf temperature.
Meyvis further illustrates a lyophilization process in which the primary drying phase is conducted using multiple shelf temperatures. After freezing, shelf temperature was gradually increased from -50℃ to -20℃ to 5℃ during primary drying. Each temperature is held constant for a defined period of time before transitioning to the next step, demonstrating that primary drying can consist of a stepwise increase of shelf temperatures with multiple hold periods (see Table 14: Lyophilization Parameters).
Therefore, it would have been obvious to one of ordinary skill in the art to apply the lyophilization method of Diluzio to prepare a freeze-dried powder of the anti-α4β7 antibody formulations recited by the issued claims, wherein the primary drying phase is further optimized to comprise a sequence of shelf temperatures rather than a constant set point as taught by Velradi. One of ordinary skill in the art would have been motivated to do so since the lyophilization process steps described by Diluzio –freezing, annealing, refreezing, primary drying, and secondary drying—can be used to prepare a stable, freeze-dried anti-α4β7 antibody formulation such as one having ≤2.5% moisture content, a reconstitution time of ≤20 minutes, and ≤ 2.5% of aggregates. Further, the primary drying phase of the freeze-drying cycle can be optimized by applying a sequence of shelf temperatures up to the end of the primary drying phase in order to reduce the duration of the primary drying phase while maintain the product integrity as taught by Velaradi. Meyvis in particular exemplifies a primary drying phase consisting of a stepwise increase of shelf temperatures with multiple hold periods. Accordingly, the primary drying phase can be conducted using a sequence of increasing shelf-temperatures rather than a single constant shelf temperature. Shelf temperatures and chamber pressures during each lyophilization step—including freezing, annealing, refreezing, primary drying, and secondary drying—are recognized in the prior art as results-effective variables. The courts have stated that "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimal lyophilization parameters including shelf temperatures and chamber pressures of each step, thereby arriving at the specific embodiments of the instant claims, including a stepwise primary drying phase initiated at the glass transition temperature of the anti-α4β7 antibody formulation. Moreover, the “wherein clauses” reciting expected stability of the lyophilized or reconstituted formulation in claims 1, 2, 5-7, and 1-15 are statements of intended result and, as such, do not impart patentable weight. Therefore, one of ordinary skill in the art would reasonably expect that a stable, freeze-dried anti-α4β7 antibody formulation of the issued claims can be prepared using the lyophilization method disclosed by Diluzio, wherein the primary drying phase is further modified to comprise a sequence of shelf temperatures rather as taught by Velaradi and exemplified by Meyvis.
Claims 1 and 4-7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 12024561B2 in view of Diluzio et al (US20140377251A1), hereinafter Diluzio, Velaradi et al (US8800162B2), hereinafter Velaradi, and Meyvis et al (US20160090424A1), hereinafter Meyvis.
The issued claims recite a pharmaceutical formulation comprising 60 mg/ml of the anti-α4β7 antibody vedolizumab, buffer, 20 -90 mM sodium chloride, and 0.6 mg/ml polysorbate 80 wherein the formulation is devoid of free amino acid and sugar and has a pH of 6.0-7.0. The formulation is stable and maintains at least 95% of monomeric content of the antibody and controls the low molecular weight species to less than 1% in the formulation, when stored at 40° C. for four weeks (issued claim 3) The pharmaceutical formulation can be a lyophilized formulation.
The issued claims do not specifically recite a method for making the lyophilized formulation comprising the anti-α4β7 antibody.
However, Diluzio discloses a method of preparing a stable, freeze-dried anti-α4β7 antibody formulation via a lyophilization process involving three main steps: freezing, primary drying, and secondary drying (Para. 0144). In general, the formulation is frozen at a temperature of about −30° C. or less such as −40° C. or −50° C) (Para. 0146). Once the formulation is frozen, the atmospheric pressure is reduced and the temperature is adjusted to allow removal of the frozen solvent through sublimation during primary drying (Para. 0144). Primary drying temperatures are selected as approximately 10-50℃ above freezing temperatures, which results in primary drying temperatures that can fall within approximately -30℃ to 0℃ (Para. 0146). The temperature is then raised to remove any solvent that is still bound to the dry formulation by evaporation during secondary drying, which is conducted at a temperature that is above the freezing temperature of the liquid formulation such as about 10° to about 50° C. In one particular embodiment, the temperature for secondary drying is ambient temperature, e.g., 20-30° C. The time for secondary drying should be sufficient to reduce the amount of moisture to <5% (Para. 0144 and Para. 0151). An optional step after freezing and before primary drying is annealing, wherein the shelf temperature is raised above the glass transition temperature of the formulation for a short period of time then lowered again to below the glass transition temperature of the formulation. An annealing step of an anti-α4β7 antibody formulation can be at about −30° C. to about −10° C. or about −25° C. to about −15° C. In one particular embodiment, an annealing temperature for an α4β7 antibody formulation is about −20° C (Para. 0150). An exemplary lyophilization cycle includes freezing at about −45° C, annealing at about −20° C, refreezing at about −45° C, primary drying at about −24° C and 150 mTorr, and secondary drying at about 27° C and 150 mTorr (Para. 0152). Lyophilized vials of anti-α4β7 antibody are stored at −70° C., −20° C., 2-8° C. or 25° C. for desired periods of time (Para. 0203). The anti-α4β7 antibody formulations can have ≦1.0% aggregate or ≦0.5% aggregate (Para. 0112). Acceptable quality levels an anti-α4β7 antibody dry, solid formulation include ≦2.5% moisture content, ≦20 minutes reconstitution time, and ≦ 2.5% of aggregates (Para. 0101, 0110, and 0195).
Velradi further teaches that the primary drying phase of a freeze-drying cycle can be optimized by calculating and applying a sequence of shelf temperatures up to the end of the primary drying phase in order to maximize a sublimation rate of the product and maintain the product temperature below a maximum allowable product temperature (Abstract). In other words, adjusting the shelf temperature through a sequence of heating steps reduces the duration or primary drying while maintaining the product at a safe temperature level (Col. 4, Ln. 65-67). Thus, primary drying can be conducted using a sequence of shelf-temperatures rather than at constant shelf temperature.
Meyvis further illustrates a lyophilization process in which the primary drying phase is conducted using multiple shelf temperatures. After freezing, shelf temperature was gradually increased from -50℃ to -20℃ to 5℃ during primary drying. Each temperature is held constant for a defined period of time before transitioning to the next step, demonstrating that primary drying can consist of a stepwise increase of shelf temperatures with multiple hold periods (see Table 14: Lyophilization Parameters).
Therefore, it would have been obvious to one of ordinary skill in the art to apply the lyophilization method of Diluzio to prepare a freeze-dried powder of the anti-α4β7 antibody formulations recited by the issued claims, wherein the primary drying phase is further optimized to comprise a sequence of shelf temperatures rather than a constant set point as taught by Velradi. One of ordinary skill in the art would have been motivated to do so since the lyophilization process steps described by Diluzio –freezing, annealing, refreezing, primary drying, and secondary drying—can be used to prepare a stable, freeze-dried anti-α4β7 antibody formulation such as one having ≤2.5% moisture content, a reconstitution time of ≤20 minutes, and ≤ 2.5% of aggregates. Further, the primary drying phase of the freeze-drying cycle can be optimized by applying a sequence of shelf temperatures up to the end of the primary drying phase in order to reduce the duration of the primary drying phase while maintain the product integrity as taught by Velaradi. Meyvis in particular exemplifies a primary drying phase consisting of a stepwise increase of shelf temperatures with multiple hold periods. Accordingly, the primary drying phase can be conducted using a sequence of increasing shelf-temperatures rather than a single constant shelf temperature. Shelf temperatures and chamber pressures during each lyophilization step—including freezing, annealing, refreezing, primary drying, and secondary drying—are recognized in the prior art as results-effective variables. The courts have stated that "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimal lyophilization parameters including shelf temperatures and chamber pressures of each step, thereby arriving at the specific embodiments of the instant claims, including a stepwise primary drying phase initiated at the glass transition temperature of the anti-α4β7 antibody formulation. Moreover, the “wherein clauses” reciting expected stability of the lyophilized or reconstituted formulation in claims 1, 2, 5-7, and 1-15 are statements of intended result and, as such, do not impart patentable weight. Therefore, one of ordinary skill in the art would reasonably expect that a stable, freeze-dried anti-α4β7 antibody formulation of the issued claims can be prepared using the lyophilization method disclosed by Diluzio, wherein the primary drying phase is further modified to comprise a sequence of shelf temperatures rather as taught by Velaradi and exemplified by Meyvis.
Claims 1-10 and 12-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, and 7-15 of copending Application No. 18036546 in view of Diluzio et al (US20140377251A1), hereinafter Diluzio, Velaradi et al (US8800162B2), hereinafter Velaradi, and Meyvis et al (US20160090424A1), hereinafter Meyvis.
This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite a pharmaceutical formulation comprising 60 mg/mL of the anti-α4β7 antibody vedolizumab, a histidine-phosphate buffer, arginine, salt, and a surfactant (co-pending claims 1 and 2), wherein the formulation is stable when stored at 40C or 25C for 4 weeks (co-pending claim 3). The vedolizumab formulation can be a lyophilized formulation (co-pending claim 8).
The issued claims do not specifically recite a method for making the lyophilized formulation comprising the anti-α4β7 antibody.
However, Diluzio discloses a method of preparing a stable, freeze-dried anti-α4β7 antibody formulation via a lyophilization process involving three main steps: freezing, primary drying, and secondary drying (Para. 0144). In general, the formulation is frozen at a temperature of about −30° C. or less such as −40° C. or −50° C) (Para. 0146). Once the formulation is frozen, the atmospheric pressure is reduced and the temperature is adjusted to allow removal of the frozen solvent through sublimation during primary drying (Para. 0144). Primary drying temperatures are selected as approximately 10-50℃ above freezing temperatures, which results in primary drying temperatures that can fall within approximately -30℃ to 0℃ (Para. 0146). The temperature is then raised to remove any solvent that is still bound to the dry formulation by evaporation during secondary drying, which is conducted at a temperature that is above the freezing temperature of the liquid formulation such as about 10° to about 50° C. In one particular embodiment, the temperature for secondary drying is ambient temperature, e.g., 20-30° C. The time for secondary drying should be sufficient to reduce the amount of moisture to <5% (Para. 0144 and Para. 0151). An optional step after freezing and before primary drying is annealing, wherein the shelf temperature is raised above the glass transition temperature of the formulation for a short period of time then lowered again to below the glass transition temperature of the formulation. An annealing step of an anti-α4β7 antibody formulation can be at about −30° C. to about −10° C. or about −25° C. to about −15° C. In one particular embodiment, an annealing temperature for an α4β7 antibody formulation is about −20° C (Para. 0150). An exemplary lyophilization cycle includes freezing at about −45° C, annealing at about −20° C, refreezing at about −45° C, primary drying at about −24° C and 150 mTorr, and secondary drying at about 27° C and 150 mTorr (Para. 0152). Lyophilized vials of anti-α4β7 antibody are stored at −70° C., −20° C., 2-8° C. or 25° C. for desired periods of time (Para. 0203). The anti-α4β7 antibody formulations can have ≦1.0% aggregate or ≦0.5% aggregate (Para. 0112). Acceptable quality levels an anti-α4β7 antibody dry, solid formulation include ≦2.5% moisture content, ≦20 minutes reconstitution time, and ≦ 2.5% of aggregates (Para. 0101, 0110, and 0195).
Velradi further teaches that the primary drying phase of a freeze-drying cycle can be optimized by calculating and applying a sequence of shelf temperatures up to the end of the primary drying phase in order to maximize a sublimation rate of the product and maintain the product temperature below a maximum allowable product temperature (Abstract). In other words, adjusting the shelf temperature through a sequence of heating steps reduces the duration or primary drying while maintaining the product at a safe temperature level (Col. 4, Ln. 65-67). Thus, primary drying can be conducted using a sequence of shelf-temperatures rather than at constant shelf temperature.
Meyvis further illustrates a lyophilization process in which the primary drying phase is conducted using multiple shelf temperatures. After freezing, shelf temperature was gradually increased from -50℃ to -20℃ to 5℃ during primary drying. Each temperature is held constant for a defined period of time before transitioning to the next step, demonstrating that primary drying can consist of a stepwise increase of shelf temperatures with multiple hold periods (see Table 14: Lyophilization Parameters).
Therefore, it would have been obvious to one of ordinary skill in the art to apply the lyophilization method of Diluzio to prepare a freeze-dried powder of the anti-α4β7 antibody formulations recited by the issued claims, wherein the primary drying phase is further optimized to comprise a sequence of shelf temperatures rather than a constant set point as taught by Velradi. One of ordinary skill in the art would have been motivated to do so since the lyophilization process steps described by Diluzio –freezing, annealing, refreezing, primary drying, and secondary drying—can be used to prepare a stable, freeze-dried anti-α4β7 antibody formulation such as one having ≤2.5% moisture content, a reconstitution time of ≤20 minutes, and ≤ 2.5% of aggregates. Further, the primary drying phase of the freeze-drying cycle can be optimized by applying a sequence of shelf temperatures up to the end of the primary drying phase in order to reduce the duration of the primary drying phase while maintain the product integrity as taught by Velaradi. Meyvis in particular exemplifies a primary drying phase consisting of a stepwise increase of shelf temperatures with multiple hold periods. Accordingly, the primary drying phase can be conducted using a sequence of increasing shelf-temperatures rather than a single constant shelf temperature. Shelf temperatures and chamber pressures during each lyophilization step—including freezing, annealing, refreezing, primary drying, and secondary drying—are recognized in the prior art as results-effective variables. The courts have stated that "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimal lyophilization parameters including shelf temperatures and chamber pressures of each step, thereby arriving at the specific embodiments of the instant claims, including a stepwise primary drying phase initiated at the glass transition temperature of the anti-α4β7 antibody formulation. Moreover, the “wherein clauses” reciting expected stability of the lyophilized or reconstituted formulation in claims 1, 2, 5-7, and 1-15 are statements of intended result and, as such, do not impart patentable weight. Therefore, one of ordinary skill in the art would reasonably expect that a stable, freeze-dried anti-α4β7 antibody formulation of the co-pending claims can be prepared using the lyophilization method disclosed by Diluzio, wherein the primary drying phase is further modified to comprise a sequence of shelf temperatures rather as taught by Velaradi and exemplified by Meyvis.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/ Examiner, Art Unit 1641
/MISOOK YU/ Supervisory Patent Examiner, Art Unit 1641
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