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 .
Applicant’s amendments and remarks filed 8-7-26 and 7-22-26 are acknowledged.
Claims 1, 7, 8, 11, 12, 15, 16, 20, 21 and 22-31 are pending.
Upon consideration of applicant’s claim amendments the species of buffer under consideration has been extended to include succinate and glycine.
Claims 1, 7, 8, 11, 12, 15, 16, 20, 21, 22-29 and 31 are under examination as they read on a formulation wherein
the species of buffer under consideration is “glutamate;” “succinate;” or “glycine;”
the species of saccharide under consideration is “sucrose;”
the species of target cell surface antigen is “DLL3;” and
the species of target cell surface antigen CDRs is SEQ ID NOs: 67-72, the species of VH/VL is SEQ ID NOs: 73/74, and the species of bispecific construct is SEQ ID NOs: 76 or 77.
Claim 30 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3-2-26.
The prior rejection under 35 USC § 112(b) has been withdrawn in view of applicant’s claim amendments.
The prior obviousness-type double patenting rejections over co-pending Application Nos. 17046662 (now corresponding to issued patent 12679865); 17921793; and 18022685 have been withdrawn in view of applicant’s claim amendments.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1, 7, 8, 11, 12, 15, 16, 21, 22 and 23-29 stand rejected, and new claim 31 is rejected under 35 U.S.C. 102(a)(1)/(a)(2) as anticipated by Abel et al. (WO2018204907, cited on an IDS) as evidenced by Brian Kelley (mAbs 1:5, 443-452; September/October 2009, of record).
Alternatively, insofar as applicant may attempt to argue the teachings of Abel are not clearly anticipatory for whatever reason, the instant claims are rejected, in the alternative, under 35 U.S.C. 103 as obvious over the teachings of Abel et al. further in view of Elder et al. (“Antimicrobial Preservatives Part Two: Choosing a Preservative,” January 1, 2012, pages 1-14, obtained from the internet 9-11-26 and cited herewith); Flora et al. (J. Pharm. Pharmacol. 1980, 32: 577, cited herewith); and Clyde Schultz (J Med Therap, 2017, Volume 1(1): 1-2, cited herewith).
The claims are anticipated by Abel as evidenced by Kelley:
As a preliminary matter, note that it would be well understood by the ordinarily skilled artisan that the typical antibody purification process often begins with antibody titers ranging from 1-5 g/L, or even 10-13 g/L (depending on the culture time), and that the multistep process leading to production of the “Bulk Drug Substance” typically involves multiple steps which act to isolate and concentrate the antibody which will eventually be stored in said concentrated state in multiple containers that can be shipped as needed to various “drug product manufacturing sites” as evidenced by Kelley at page 443-444 bridging paragraph – col. bridging paragraph and Fig. 1.
Likewise, it was also common knowledge in the art that the typical activities of a “drug product manufacturing site” involve “fill-finish” steps such as vialing of the drug substance and distribution to the point of care as further evidenced by Kelley at pages 443 and 447, last full paragraphs on each.
The teachings of Abel set forth below are to be viewed with the common knowledge of one of ordinary skill in the art illustrated by the teachings of Kelley set forth above in mind.
At paragraph [12] Abel teaches pharmaceutical compositions for, “the safe, quantitative and optionally prolonged administration of protein-based pharmaceuticals such as bispecific antibody constructs including bispecific T cell engaging antibody constructs, typically via the i.v. route, is challenging. To this end, in the context of the present invention, a pharmaceutical composition is provided, comprising
i. a bispecific antibody construct, binding to a target cell surface antigen via a first binding domain and to the T cell surface antigen CD3 via a second binding domain, wherein the chain antibody construct is present in a concentration in the range from 0.5 μg/ml to 20 mg/ml, preferably 0.5 μg/ml to 10 or 5 mg/ml….”
(emphasis added).
Similarly, at paragraph [13] Abel teaches, “It is envisaged in the context of the present invention that the bispecific antibody construct is present at a concentration in the range selected from the list consisting of …(d) 0.5 μg/ml to 20 mg/ml, preferably 0.5 μg/ml to 10 or 5 mg/ml at a pH of 4.0 to 7.5, wherein the bispecific antibody comprises a third binding domain which comprises two polypeptide monomers, each comprising a hinge, a CH2 and a CH3 domain, wherein said two polypeptide monomers are fused to each other via a peptide linker, and wherein said third binding domain comprises in an amino to carboxyl order:
hinge-CH2-CH3-linker-hinge-CH2-CH3.”
(emphasis added).
Likewise, in paragraph [56] Abel teaches:
“…depending for example on the bispecific antibody concentration type, and optionally the pH and the presence of a further complementing stabilizing agent, the pharmaceutical composition according to the present invention is stable. Therein, the first binding domain as described herein (targeting domain) is of less importance because the stabilizing action of a preservative and optional further stabilizing complementing excipient, such as citrate, is primarily associated with interaction with the second binding domain (CD3 binding domain). Advantageously, the preservative may serve to physically and microbiologically stabilize the pharmaceutical composition during storage, e.g. in frozen state, and -after optional pH adjustment and/or dilution- when administered. Hence, conveniently the same pharmaceutical composition may be used, despite optional pH adjustment, e.g. from low pH such as 4.0 to 6.5 to a neutral pH from 6.5 to 7.5, and dilution for the purpose of i.v. administration. Throughout, the bispecific antibody construct concentration is, however, in range of 0.5 μg/ml to 5 mg/ml, or in some circumstances, in the range of 0.3 μg/ml to 10, 20, or even 30 mg/ml. Thereby, pharmaceutical composition comprising containers such as i.v. infusion bags may be only required to be exchanged with longer time intervals such as 3, 4, 5, 6, 7, 8, 9 , 10, 11 , 12, 13 or even 14 days due to reduced lack of microbial contamination, which significantly increases patient comfort.”
(emphasis added).
With respect to the format and conditions under which the antibodies of Abel may be provided to the end user, the use of “lyophilization” / “a lyophilizate” is described at paragraphs [39] and [45] (emphasis added):
“[39] It is further envisaged in the context of the present invention that the bispecific antibody construct is provided as a lyophilisate, the lyophilisate preferably comprising a lyoprotector, a buffer and/or a surfactant, and wherein the lyophilisate is reconstituted by a diluent, comprising a preservative and preferably comprising a buffer and/or an excipient.”
“[45] Also envisaged in the context of the present invention is a kit comprising the bispecific antibody construct as a lyophilisate, the lyophilisate preferably comprising a lyoprotector, a buffer and/or a surfactant, and a diluent, comprising a preservative and preferably comprising a buffer and/or an excipient according to the present invention.”
The concept of preparing a pharmaceutical composition that will eventually comprise a preservative as an initial lyophilisate which is then reconstituted by a diluent comprising a preservative and preferably comprising a buffer and/or excipient, such as succinate and/or glycine is echoed in claim 29 of Abel:
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Dependent claim 6 for example recites: "… the diluent is a buffer comprising a salt selected from the group consisting of phosphate, acetate, citrate, succinate and tartrate, and/or wherein the buffer comprises histidine, glycine, TRIS glycine, Tris, or mixtures thereof.”
With respect to providing formulation stability, Abel teaches the “Polyol” sucrose is capable of doing so for both liquid and lyophilized formulations at paragraph 271:
“[0271] Polyols include sugars, e.g., mannitol, sucrose, and sorbitol and polyhydric alcohols such as, for instance, glycerol and propylene glycol, and, for purposes of discussion herein, polyethylene glycol (PEG) and related substances. Polyols are kosmotropic. They are useful stabilizing agents in both liquid and lyophilized formulations to protect proteins from physical and chemical degradation processes. Polyols also are useful for adjusting the tonicity of formulations. Among polyols useful in select embodiments of the invention is mannitol, commonly used to ensure structural stability of the cake in lyophilized formulations. It ensures structural stability to the cake. It is generally used with a lyoprotectant, e.g., sucrose. Sorbitol and sucrose are among preferred agents for adjusting tonicity and as stabilizers to protect against freeze-thaw stresses during transport or the preparation of bulks during the manufacturing process. Reducing sugars (which contain free aldehyde or ketone groups), such as glucose and lactose, can glycate surface lysine and arginine residues. Therefore, they generally are not among preferred polyols for use in accordance with the invention. In addition, sugars that form such reactive species, such as sucrose, which is hydrolyzed to fructose and glucose under acidic conditions, and consequently engenders glycation, also is not among preferred polyols of the invention in this regard. PEG is useful to stabilize proteins and as a cryoprotectant and can be used in the invention in this regard.”
(emphasis added).
Similar teachings are also set forth at paragraph 322:
“[322] Polyols are useful stabilizing agents in both liquid and lyophilized formulations to protect proteins from physical and chemical degradation processes, and are also useful for adjusting the tonicity of formulations. Polyols include sugars, e.g., mannitol, sucrose, and sorbitol and polyhydric alcohols such as, for instance, glycerol and propylene glycol, and, for purposes of discussion herein, polyethylene glycol (PEG) and related substances. Mannitol is commonly used to ensure structural stability of the cake in lyophilized formulations. It ensures structural stability to the cake. It is generally used with a lyoprotectant, e.g., sucrose. Sorbitol and sucrose are commonly used agents for adjusting tonicity and as stabilizers to protect against freeze-thaw stresses during transport or the preparation of bulks during the manufacturing process. PEG is useful to stabilize proteins and as a cryoprotectant.”
(emphasis added).
As to the buffering agent, at paragraphs 315-316 Abel teaches the use of, inter alia, “glutamate” at concentration range at set forth in the instant claims (emphasis added):
“[315] The pharmaceutical composition of the invention further comprises a buffer, which may be selected from the group consisting of potassium phosphate, acetic acid/sodium acetate, citric acid/sodium citrate, succinic acid/sodium succinate, tartaric acid/sodium tartrate, histidine/histidine HCI, glycine, Tris, glutamate, acetate and mixtures thereof, and in particular from potassium phosphate, citric acid/sodium citrate, succinic acid, histidine, glutamate, acetate and combinations thereof.
[316] Suitable buffer concentrations encompass concentrations of about 200 mM or less, such as about 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 80, 70, 60, 50, 40, 30, 20, 10 or 5 mM. The skilled person will be readily able to adjust the buffer concentrations in order to provide for stability of the pharmaceutical composition as described herein. Envisaged buffer concentrations in the pharmaceutical composition of the invention specifically range from about 5 to about 200 mM, preferably from about 5 to about 100 mM, and more preferably from about 10 to about 50 mM.”
Finally, with respect to ensuring that the bispecific antibody formulation does not adhere to surfaces thereby further ensuring protein stability, Abel teaches the following at paragraph 272:
“[272] Embodiments of the antibody construct of the invention formulations further comprise surfactants. Protein molecules may be susceptible to adsorption on surfaces and to denaturation and consequent aggregation at air-liquid, solid-liquid, and liquid-liquid interfaces. These effects generally scale inversely with protein concentration. These deleterious interactions generally scale inversely with protein concentration and typically are exacerbated by physical agitation, such as that generated during the shipping and handling of a product. Surfactants routinely are used to prevent, minimize, or reduce surface adsorption. Useful surfactants in the invention in this regard include polysorbate 20, polysorbate 80, other fatty acid esters of sorbitan polyethoxylates, and poloxamer 188. Surfactants also are commonly used to control protein conformational stability. The use of surfactants in this regard is protein-specific since, any given surfactant typically will stabilize some proteins and destabilize others.”
(emphasis added).
Likewise, at paragraph 329 Abel teaches suitable concentrations of sucrose, polysorbate 20, polysorbate 80 and combinations thereof for use in formulating bispecific antibody compositions:
“[329] Particularly useful excipients for formulating the pharmaceutical composition include sucrose, trehalose, mannitol, sorbitol, arginine, lysine, polysorbate 20, polysorbate 80, poloxamer 188, pluronic and combinations thereof. Said excipients may be present in the pharmaceutical composition in different concentrations, as long as the composition exhibits the desirable properties as exemplified herein, and in particular promotes stabilization of the contained bispecific single chain antibody constructs. For instance, sucrose may be present in the pharmaceutical composition in a concentration between 2% (w/v) and 12% (w/v), i.e. in a concentration of 12% (w/v), 11% (w/v), 10% (w/v), 9% (w/v), 8% (w/v), 7% (w/v), 6% (w/v), 5% (w/v), 4% (w/v), 3% (w/v) or 2% (w/v). Preferred sucrose concentrations range between 4 % (w/v) and 10% (w/v) and more preferably between 6 % (w/v) and 10% (w/v). Polysorbate 80 may be present in the pharmaceutical composition in a concentration between 0.001% (w/v) and 0.5% (w/v), i.e. in a concentration of 0.5% (w/v), 0.2% (w/v), 0.1% (w/v), 0.08% (w/v), 0.05% (w/v), 0.02% (w/v), 0.01% (w/v), 0.008% (w/v), 0.005% (w/v), 0.002% (w/v) or 0.001% (w/v). Preferred Polysorbate 80 concentrations range between 0.002% (w/v) and 0.5% (w/v), and preferably between 0.005% (w/v) and 0.02% (w/v).”
(emphasis added).
Among the bispecific antibody constructs taught by Abel, a preferred construct comprises a “third domain” which is a “half-life extension” (“HLE”) domain in the form of hinge-CH2-CH3-linker-hinge-CH2-CH3 (see paragraphs 12-14; 225).
According to Abel at paragraph 128, an advantage of such a format is that it “…It is an envisaged characteristic of the antibody constructs according to the present invention to have superior affinity characteristics in comparison to other HLE formats. Such a superior affinity, in consequence, suggests a prolonged half-life in vivo. The longer half-life of the antibody constructs according to the present invention may reduce the duration and frequency of administration which typically contributes to improved patient compliance. This is of particular importance as the antibody constructs of the present invention are particularly beneficial for highly weakened or even multimorbide cancer patients.”
One particular bispecific antibody described by Abel binds to CD3 and to the tumor antigen “DLL3.” (see, e.g., paragraphs 233, 234, 236 and SEQ ID NOs: 94-104 in Table 5 of Abel).
An alignment of Abel SEQ ID NO: 104, and SEQ ID NO: 77 of the instant specification, is shown below. Note that SEQ ID NOs: 1-6, 67-72, 73 and 74 of the instant claims are encompassed by Abel SEQ ID NO: 104.
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Finally, at paragraph 341 Abel teaches “The pharmaceutical compositions described herein are particularly useful for parenteral administration, e.g., subcutaneous or Intravenous delivery, for example by injection such as bolus injection, or by infusion such as continuous infusion….”
Thus, the teachings of Abel anticipate the instant claims.
The obviousness rejection under 35 USC § 103:
The teachings of Abel are set forth above.
Insofar as applicant may attempt to argue the teachings of Abel are not clearly anticipatory for whatever reason, the instant claims are rejected, in the alternative, under 35 U.S.C. 103 as obvious over the teachings of Abel et al. further in view of Elder, Flora and Schultz as described below.
Regarding the “Physical Stability of Preservatives” at page 6, Elder teaches the following (emphasis added):
“Preservative content in products can be depleted during manufacture, storage or use.
The parabens [13,45,46], benzoic acid [15], benzyl alcohol [16], 2-phenoxyethanol [42], m-cresol [25], chlorocresol [19] and chlorbutanol [44] are all volatile to greater or lesser extents. This renders them susceptible to losses by sublimation or evaporation during manufacture or throughout product life. m-Cresol [25] and phenol [26] are not suitable as preservatives for preparations that need to be lyophilized due to their volatility. In addition, if any of the container / closure components are permeable to gases, e.g. plastic bottles or elastomeric closures, then this can result in the depletion of volatile preservatives.”
Likewise, Flora describes how certain parabens and variety of other small molecule preservatives are considered not suitable for lyophilized products due to their loss during the freeze drying process:
“Recently the loss of two preservatives, methylparaben (MP) and propylparaben (PP) was encountered during freeze drying of an aqueous solution in our laboratory. Avis (1970) has noted that volatile antibacterial preservatives (benzyl alcohol, phenol and chlorobutanol)
are not suitable for lyophilized products. However, we are unaware of any reports describing
the loss of MP or PP during lyophilization. This report describes the factors influencing the loss of these antibacterial perservatives during freeze drying.” (see first paragraph on page 577).
Given the teachings of Abel in view of Elder and Flora it would have been obvious to the ordinarily skilled artisan that in one embodiment Abel is teaching the provision of their bispecific antibody construct in the form of a lyophilisate comprising a lyoprotector, a buffer and/or a surfactant, wherein said lyophilisate will be reconstituted with a diluent that comprises a preservative, a buffer and/or an excipient.
Consistent with a plain language reading of the teachings of Abel in view of Elder and Flora, it would have been obvious to one of ordinary skill in the art that omitting a preservative from the lyophilisate would allow for greater consistency with respect to the reconstituted formulation since preservatives were expected to be lost via sublimination from the lyophilisate dependent on variety of molecular (e.g., the chemical structure of the preservative and its interaction with other components of the formulation) and/or environmental variables (e.g., the manner in which the freeze drying occurred, the type of lyophilisate storage container). Moreover, knowing that (i) sterilizing filtration of the antibody formulation can occur prior to lyophilization as taught, e.g., at [266] of Abel, and (ii) that microbial growth is commonly suppressed in appropriately produced solid products (see Schultz at Abstract and 1st paragraph for example), the ordinarily skilled artisan would have had a reasonable expectation of successfully following the teachings of Abel at paragraphs [39], [45] and claim 29 to prepare a lyophilisate comprising a lyoprotector, a buffer and/or a surfactant, wherein said lyophilisate will be reconstituted with a diluent that comprises a preservative, a buffer and/or an excipient.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 1, 7, 8, 11, 12, 15, 16, 20, 21, 22-29 and 31 are rejected under 35 U.S.C. 103 as obvious over Abel et al. (WO2018204907, cited on an IDS) as evidenced by Kelley et al. (of record) in view of Elder et al. (“Antimicrobial Preservatives Part Two: Choosing a Preservative,” January 1, 2012, pages 1-14, obtained from the internet 9-11-26 and cited herewith); Flora et al. (J. Pharm. Pharmacol. 1980, 32: 577, cited herewith); and Clyde Schultz (J Med Therap, 2017, Volume 1(1): 1-2, cited herewith) as applied to claims 1, 7, 8, 11, 12, 15, 16, 21, 22-29 and 31 above, and further in view of Gadgil et al. (J Pharm Sci 96:2607–2621, 2007, of record).
The teachings of Abel as evidenced by Kelley in view of Elder, Flora and Schultz are set forth above.
Insofar as applicant may attempt to argue that the teachings of Abel as evidenced by Kelly in view of Elder, Flora and Schultz do not render the claimed invention obvious, e.g., because they do not explicitly state “at least 20 mg/mL,” the claimed formulations could also be said to be obvious in view of the teachings of Abel, e.g., at paragraphs [12], [13] and [56] as set forth above, wherein Abel sets forth multiple bispecific antibody construct concentration ranges including ranges extending to 10 mg/mL, 20 mg/mL or even 30 mg/mL.
Furthermore, insofar as applicant may attempt to argue that certain teachings of Abel at paragraph 271 lines 29-321 could be interpreted to contradict the anticipatory use of sucrose in a formulation having a pH of 4-6, it likewise would have been obvious to one of ordinary skill in the art; moreover, one of ordinary skill in the art would have been motivated to use a saccharide such a sucrose as a lyoprotectant as taught by Abel.
This is because, as described by Gadgil, “Sucrose is often used in both liquid and lyophilized protein formulations as a stabilizing agent.2,3 Sucrose is known to prevent aggregation during the freezing and annealing steps used in lyophilization cycles.4,5 In liquid formulations, sucrose improves protein stability by inhibiting irreversible aggregation and by increasing the thermal transition temperatures of proteins.6,7”
Thus, it would be obvious to one of ordinary skill in the art that, apart from the “glycation” concern, sucrose was commonly and successfully used as stabilizing agent in lyophilized formulations of antibodies.
Furthermore, despite the possibility of sucrose mediated glycation under certain conditions, as described by Gadgil at page 2619, right col., last full paragraph, “[o]ur data indicated that at 4°C sucrose does not cause glycation, even after incubation for 18 months. Since the recommended storage condition for liquid formulations is 2–8°C, sucrose could be used as a stabilizing excipient in the mildly acidic IgG formulations used in this study.”
Thus, the ordinarily skilled artisan would consider the sucrose glycation concern to be de minimis, especially when a sucrose comprising lyophilized formulation is stored at cold temperatures.
Likewise, the ordinarily skilled artisan would also have been motivated to, and would have had a reasonable expectation of successfully using a sucrose comprising formulation for the bispecific antibody formulations of Abel because several order magnitude fold dilution of sucrose would obviously occur when a bulk drug substance formulation comprising the antibody of Abel is first vialed at a drug manufacturing site, and subsequently transferred from a vial to an IV bag, and such a low concentration of sucrose in, e.g., a 250 mL saline solution comprising IV bag (see Abel at [360] and [368]) would be reasonably expected by the ordinarily skilled artisan to have no significant effect on antibody “glycation.”
When the above is taken together, it would have been obvious to one of ordinary skill in the art that even formulations of Abel comprising 10, 20 or 30 mg/mL of a bispecific antibody, such as Abel SEQ ID NO: 104, a buffer such as glutamate, a saccharide such as sucrose, a surfactant such as polysorbate 20 or 80, said formulation having a pH of 4-6, would not be reasonably expected to be substantively susceptible to glycation, e.g., even when reconstituted in as a small volume liquid sample and stored in a refrigerator prior to transfer to a 250 mL IV bag (see Abel at [360]).
Finally, insofar as Abel does not explicitly set forth a formulation of claim 1 having the precise glutamate (10 mM), sucrose (9% w/v), polysorbate 80 (0.01% w/v) and pH (4.2) set forth in claim 20, it would have been obvious for the reasons set forth above to one of ordinary skill in the art that Abel teaches preparing formulations having particular concentrations of bispecific antibody constructs in presence of particular buffer components (e.g., a glutamate buffer) at particular concentrations, particular saccharides (e.g., sucrose) at particular concentrations, particular surfactants (e.g., polysorbate 20) at particular concentrations, all present in the context of various pH ranges, and further that the exact concentrations of each of the above components would be understood by the ordinarily skilled artisan to be a result-effective variable which could obviously be manipulated to achieve a desired result, i.e., to achieve “stability” and “quantitative recovery from the administration container” of the protein biomolecule (as described, e.g., at Abel paragraph [11]).
In this regard, Applicant’s attention is further drawn to MPEP 2144.05(II)(A), Routine Optimization - Optimization Within Prior Art Conditions or Through Routine Experimentation:
“Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).”
Although this passage does not specifically point to, for example, particular antibody formulation components (e.g., particular buffers, saccharides, surfactants and pH values), this passage points to numerous general variables that affect the function of inventions, such as concentration of reagents and temperature ranges. Furthermore this passage indicates that the optimization of such variables is often an obvious activity for one of ordinary skill in the art. It is submitted that the claimed concentrations of antibody formulation components are akin to the variables discussed in the cited MPEP passage because said concentrations of antibody formulation components are optimizable variables that would be expected to affect the “stability” of a bispecific antibody construct formulation as well as the “quantitative recovery from the administration container” of a formulated bispecific antibody construct.
Given the “normal desire of scientists or artisans to improve upon what is already generally known,” it would have been prima facie obvious to one of ordinary skill in the art to optimize the concentrations of antibody formulation components disclosed in Abel to achieve, e.g., “stability” and “quantitative recovery from the administration container” of a formulated bispecific antibody construct, especially since such characteristics would obviously increase the economic value and usability of such a formulation.
Additionally, as set forth in MPEP 2144.05(II)(B), there is a Motivation to Optimize Result-Effective Variables:
… In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because "obvious to try" is not a valid rationale for an obviousness finding. However, in KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421 ("The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103."). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process.
In the instant case, the claims are drawn to antibody formulations comprising various concentrations of components (e.g., particular concentrations of buffers, saccharides and surfactants, all formulated within a particular pH range(s)), which when combined achieve a certain result such as “stability” and “quantitative recovery from the administration container” of the formulated protein biomolecule.
Accordingly, the particular concentrations of buffer, saccharide, and surfactant, all at a specified pH are recited in claim 20 are result-effective variables that achieve a recognized result; furthermore, it is submitted that since one of ordinary skill in the art would have been motivated to determine the optimum or workable ranges of said variables, the recited concentrations of buffer, saccharide, and surfactant, all at a specified pH of claim 20 were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Applicant’s arguments concerning the prior anticipation and obviousness rejections
Applicant argues “…the claim amendment amends claim 1 to recite a lyophilized pharmaceutical formulation that does not comprise a preservative and comprises a bispecific antibody construct in an amount of at least 20 mg/ml when reconstituted” and “…Abel focuses on pharmaceutical formulations that include another component as a preservative. See, for example, Abel claim 1,…” (emphasis added).
Applicant’s arguments have been considered but are not found convincing because claim 1 is drawn to “A lvophilized pharmaceutical formulation,” “…wherein the formulation has a pH of 4-5, and wherein the formulation does not comprise a preservative,” and the claim further specifies that when the lvophilized stable pharmaceutical formulation is “reconstituted” it [the lvophilized stable pharmaceutical formulation] comprises a bispecific antibody construct in an amount of at least 20 mg/mL, a buffer, a saccharide and a surfactant.
Thus, applicant’s argument is not found convincing because applicant is arguing a limitation not claimed in that the reconstituted lvophilized stable pharmaceutical formulation is set forth as comprising a bispecific antibody construct in an amount of at least 20 mg/mL, a buffer, a saccharide and a surfactant which is open-ended meaning that the reconstituted lvophilized stable pharmaceutical formulation may further comprise additional components including, e.g., one or more preservatives.
Claims 1, 7, 8, 11, 12, 15, 16, 21, 22, 23, 24 and 25 stand provisionally rejected, and new claim 31 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20 and 26 of copending Application No. 19109730 (reference application), or as being unpatentable over the combination of reference claims (20 and 26) in view of reference claims 2, 10, 11 and 27, essentially for the reasons of record.
Applicant asserts the rejection set forth above should be held in abeyance until all other issues in this application are resolved.
Obviousness type double patenting rejections, whether provisional or not, cannot be held in abeyance. A double patenting rejection can be overcome, e.g., by a convincing rebuttal of the merits of the rejection, by amending the claims such that they are no longer anticipated and/or rendered obvious by the reference claims or by filing a proper terminal disclaimer.
Claims 26-29 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over reference claim 26 of copending Application No. 19109730 as applied to instant claims 1, 2, 5, 7, 8, 11, 12, 15, 16, 18, 21, 22, 23, 24, 25 and 31 as set forth above, and further in view of Abel et al. (WO2018204907) and Giffin et al. (J Thorac Oncol., P3.12-03, October 2018, page S971, of record), essentially for the reasons of record.
Applicant asserts the rejection set forth above should be held in abeyance until all other issues in this application are resolved.
Obviousness type double patenting rejections, whether provisional or not, cannot be held in abeyance. A double patenting rejection can be overcome, e.g., by a convincing rebuttal of the merits of the rejection, by amending the claims such that they are no longer anticipated and/or rendered obvious by the reference claims or by filing a proper terminal disclaimer.
Claim 1, 7, 8, 11, 12, 15, 16, 21, 22 and 23-29 stand provisionally rejected, and new claim 31 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 28-30, 32, 37, 38, 41, 45, of copending Application No. 18024893 (reference application) as evidenced by Brian Kelley (mAbs 1:5, 443-452; September/October 2009, of record) and further in view of Giffin et al. (J Thorac Oncol., P3.12-03, October 2018, page S971, of record), essentially for the reasons of record.
Applicant argues as follows: “Applicant notes the claims herein recite lyophilized pharmaceutical formulations, and the methods of the '893 reference application are not merely methods of making the lyophilized pharmaceutical formulation of the claims herein. The claims as amended are therefore distinct from the claims of the reference application”
Applicant’s argument has been considered but has not been found convincing essentially for the reasons of record. In particular, by contrast to applicant’s argument, reference claim 1 and dependent claims thereof are all “methods of making the lyophilized pharmaceutical formulation of the claims herein.” Thus, the rejection stands as set forth previously essentially for the reasons of record.
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
1 “In addition, sugars that form such reactive species, such as sucrose, which is hydrolyzed to fructose and glucose under acidic conditions, and consequently engenders glycation, also is not among preferred polyols of the invention in this regard.”
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