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 election of the invention of Group I, and certain species of invention in the reply filed on 3-2-26 is acknowledged. The elected species of invention are set forth in (a)-(d) below:
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Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1, 2, 5, 7, 8, 11, 12, 15, 16, 18, 20, 21, 22, 22* and 23-30 are pending.
Claims 1, 2, 5, 7, 8, 11, 12, 15, 16, 18, 20, 21, 22, 22* and 23-29 are under examination as they read on a formulation wherein
the species of buffer under consideration is “glutamate;”
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Claim 30 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim.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.
Because the claims recite two different versions of claim 22 said claims are being considered as claim 22 (the first one) and claim 22* (the second one). Claims 22 and 22* are objected to because claims are to be numbered consecutively (see 37 CFR §1.126 ).
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 and 2 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 2 limits the invention of claim 1 to a formulation “that is lyophilized.”
The instant specification does not define or provide further guidance as to what exactly is meant by a formulation “that is lyophilized.”
According to Penguin Random House LLC, retrieved from the internet on 4-7-26 but © ≤2019, page 1 (cited herewith), a formulation that is lyophilized is one that has been dried by freezing in a high vacuum.
Thus, claim 2 given its broadest reasonable interpretation consistent with the teachings of the instant specification and the knowledge in the prior art would be understood by the skilled artisan to limit the formulation of claim 1 to a dried formulation.
However, claim 1 is drawn to “[a] stable pharmaceutical formulation comprising a bispecific antibody construct in an amount of at least 10 mg/mL, a buffer, a saccharide, and a surfactant, wherein the formulation has a pH of 4-6.”
Some ordinarily skilled artisans would argue that, while a dried formulation could theoretically be set forth in mg/mL of antibody wherein the mL is used to measure the dried lyophilizate, the drying process will necessarily vastly increase the density of the antibody construct in a mL of dried powder as compared to its 10 mg/mL density in a liquid formulation. Thus, according to this interpretation claim 2 would have to encompass > 10 mg/mL of lyophilized formulation, and claim 2 could not possible be equal to a 10 mg/mL lyophilizate.
However, others of ordinary skill in the art would argue that, in some instances, even a lyophilized formulation may be labeled as, e.g., “10 mg/mL,” but with the proviso that, e.g., assuming that a 30 mg liquid formulation of bispecific antibody at 10 mg/mL (3 mL total) were to be lyophilized in a container labeled with instructions to resuspend in 3 mL water then such a lyophilized formulation could be considered to have potential density equal to 10 mg/mL assuming resuspension in 3 mL.
Given these alternative interpretations, the metes and bounds of claim 2 would be unclear to one of ordinary skill in the art. Moreover, by the principal of claim differentiation the metes and bounds of claim 1 would also be unclear to one of ordinary skill in the art.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 2, 5, 7, 8, 11, 12, 15, 16, 18 and 21, 22, 22* and 23-29 are 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, cited herewith)
The applied reference has a common assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
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 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).
Essentially the same teachings are set forth in claims 1 and 2 of Abel:
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With respect to the format and conditions under which the antibodies of Abel may be stored, the following teachings at paragraphs [37]-[40] are instructive:
“[37] It is further envisaged that the pharmaceutical composition in the context of the present invention is a storage solution stored at -50°C, preferably at -40, -30°C or -20°C.
[38] It is also envisaged in the context of the present invention that the pharmaceutical composition provided as a storage solution stored at -50°C, preferably at -40, -30°C or -20°C comprises the bispecific antibody comprising 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.
[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.
[40] It is especially envisaged in the context of the present invention that the pharmaceutical composition is stored until use as solution, as solution in frozen state or as lyophilisate, and is then administered, optionally after dilution or reconstitution, without the need of adding further excipients selected from preservatives, stabilizers or surfactants.”
(emphasis added)
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 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.
Claims 1, 2, 5, 7, 8, 11, 12, 15, 16, 18, 20, 21, 22, 22* and 23-29 are rejected under 35 U.S.C. 103 as obvious over Abel et al. (WO2018204907, cited on an IDS) as evidenced by Brian Kelley (mAbs 1:5, 443-452; September/October 2009, cited herewith) and further in view of Gadgil et al. (J Pharm Sci 96:2607–2621, 2007, cited herewith).
As described above the teachings of Abel anticipate claims 1, 2, 5, 7, 8, 11, 12, 15, 16, 18, 21, 22, 22* and 23-29.
That said, insofar as applicant may attempt to argue that the teachings of Abel are non-anticipatory, e.g., because they do not explicitly state “at least 10 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 in an antibody formulation 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 both lyophilized and liquid 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 liquid antibody 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.”
Furthermore, the ordinarily skilled artisan would note that, even when stored at 29°C (84°F) for 6 months (which they would view as an extremely hot and long time period), there was still only a “slight increase” in antibody “HexI" value (see Gadgil at page 2611-12 bridging paragraph and Fig. 2).
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, 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.
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, 2, 5, 7, 8, 11, 12, 15, 16, 18, 21, 22, 22*, 23, 24 and 25 are provisionally 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.
Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons set forth below.
The pharmaceutical composition of reference claim 20 comprises a “liquid comprising (a) a bispecific antigen-binding molecule comprising at least three domains, wherein: a first domain binds to a target cell surface antigen, wherein the target cell surface antigen is a tumor antigen; a second domain binds to an extracellular epitope of the human and/or the Macaca CD3E chain; and a third domain comprises two polypeptide monomers, each comprising a hinge, a CH2 domain and a CH3 domain, wherein said two polypeptide monomers are fused to each other via a peptide linker, and wherein said third domain comprises in an amino to carboxyl order:hinge-CH2-CH3-linker-hinge-CH2-CH3; wherein the concentration of the bispecific antigen-binding molecule is 8 to 35 mg/ml; (b) at least one buffer agent; (c) at least one saccharide; and (d) at least one stabilizing agent…and wherein the pH of the pharmaceutical composition is in the range of 4.0 to 6.0, said pharmaceutical composition further comprising at least one surfactant is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer 188, pluronic F68, triton X- 100, polyoxyethylen, PEG 3350, PEG 4000 and combinations thereof, wherein the at least one surfactant is preferably present at a concentration in the range of 0.004 to 0.5 % (w/V), preferably in the range of 0.01 to 0.1% (w/v).”
The pharmaceutical composition of reference claim 26 comprises a “liquid comprising (a) a bispecific antigen-binding molecule comprising at least three domains, wherein: a first domain binds to a target cell surface antigen, wherein the target cell surface antigen is a tumor antigen; a second domain binds to an extracellular epitope of the human and/or the Macaca CD3E chain; and a third domain comprises two polypeptide monomers, each comprising a hinge, a CH2 domain and a CH3 domain, wherein said two polypeptide monomers are fused to each other via a peptide linker, and wherein said third domain comprises in an amino to carboxyl order:hinge-CH2-CH3-linker-hinge-CH2-CH3; wherein the concentration of the bispecific antigen-binding molecule is 8 to 35 mg/ml; (b) at least one buffer agent; (c) at least one saccharide; and (d) at least one stabilizing agent…and wherein the pH of the pharmaceutical composition is in the range of 4.0 to 6.0, said pharmaceutical composition further comprising (a) the bispecific antigen-binding molecule of any one of the preceding claims, (b) 15 mM glutamate or acetate, (c) 8% (w/V) sucrose or 8% (w/V) sucrose and 1% (w/V) hydroxypropyl-p- cyclodextrin, and (d) optionally 0.01 % (w/V) polysorbate 80, and wherein the pH of the liquid pharmaceutical composition is any value in the range of 4.0 to 5.2, preferably 4.2 to 4.6, preferably 4.3 to 4.6.”
Among the “bispecific antigen-binding molecule of any one of the preceding claims” recited in reference claim 26 is reference claim 11 which encompasses in its breadth a “first binding domain of the construct [which] comprises a VH region comprising CDR-H1, CDR-H2 and CDR-H3 and a VL region comprising CDR-L1, CDR-L2 and CDR-L3 selected from the group consisting of… (g) CDR-H1 as depicted in SEQ ID NO: 94, CDR-H2 as depicted in SEQ ID NO: 95,CDR-H3 as depicted in SEQ ID NO: 96, CDR-L1 as depicted in SEQ ID NO: 97,CDR-L2 as depicted in SEQ ID NO: 98 and CDR-L3 as depicted in SEQ ID NO: 99….,” wherein the reference CDRs of SEQ ID NOs: 94-99 are identical to the CDRs of SEQ ID NOs: 67-72 of the instant claims.
Thus, reference claims 20 and 26 anticipate instant claims 1, 5, 7, 8, 11, 12, 15, 16, 18, 21, 22, 22*, 24 and 25.
However, reference claims 20 and 26 do not explicitly state that the bispecific antigen-binding molecule comprising at least three domains of the pharmaceutical composition “is a single chain molecule” (instant claim 23) or that said pharmaceutical composition comprising a bispecific antigen-binding molecule comprising at least three domains “is lyophilized” (instant claim 2).
That said, it would have been obvious to one of ordinary skill in the art to prepare a lyophilized composition as recited in reference claim 27 for any one of the liquid pharmaceutical compositions of reference claims 20 and/or 26 since it was well known to one of ordinary skill in the art that solid lyophilized forms of liquid pharmaceutical composition are desirable given that the freeze-dried of a bispecific antibody allows for stable, long term storage and facilitates convenient shipping and distribution via ready-to-use fill-finish vials. As such the reference claims render instant claim 2 obvious as well.
Moreover, it further would have been obvious to one of ordinary skill in the art to join the vh and Vl domains of the bispecific antibody construct of reference claims 20 and/or 26 in the form of a “single chain antibody construct” as recited in instant claim 23 given that reference claim 10 specifies joining the first, second and third domains via “peptide linkers,” and it would be obvious to the ordinarily skilled artisan that having the Vh/Vl domains of reference claim 11 in the form of a single chain antibody would facilitate the production of a single polypeptide chain comprising multiple Vh/Vl domains joined said linkers.
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.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 26-29 are 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, 5, 7, 8, 11, 12, 15, 16, 18, 21, 22, 22*, 24 and 25 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, cited herewith).
The subject matter of reference claim 26 of copending Application No. 19109730 is described above.
However, said reference claims do not recite the particular SEQ ID NO: specified polypeptides set forth in instant claims 26-29.
That said, as described above 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). An advantage of such a format is that it “…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.” (see paragraph 128).
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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It would have been obvious to one of ordinary skill in the art contemplating production of the pharmaceutical composition of reference claim 26 to use Abel SEQ ID NO: 104 as a source for the bispecific antigen-binding molecule comprising at least three domains, wherein: a first domain binds to a target cell surface antigen, wherein the target cell surface antigen is a tumor antigen, such as “DLL3”; a second domain binds to an extracellular epitope of the human and/or the Macaca CD3E chain; and a third domain comprises two polypeptide monomers, each comprising a hinge, a CH2 domain and a CH3 domain, wherein said two polypeptide monomers are fused to each other via a peptide linker, and wherein said third domain comprises in an amino to carboxyl order:hinge-CH2-CH3-linker-hinge-CH2-CH3 of reference claim 26 because bispecific DLL3- and CD3- targeted antibodies having a prolonged serum half-life were believed in the art to effectively treat Small cell lung cancer (SCLC) with a reasonable expectation of success consistent with the teachings of Giffin et al. (J Thorac Oncol., P3.12-03, October 2018, page S971, cited herewith, see full document).
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.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 5, 7, 8, 11, 15, 18, 21 and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 14, 18, 26-28 and 40 of copending Application No. 17046662 (reference application) as evidenced by Brian Kelley (mAbs 1:5, 443-452; September/October 2009, cited herewith) and further in view of Giffin et al. (J Thorac Oncol., P3.12-03, October 2018, page S971, cited herewith).
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” (see 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 (see Kelley at pages 443 and 447, last full paragraphs on each).
Reference claims 1, 14, 18, 26-28 and 40 are reproduced below:
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It would have been prima facie obvious to one of ordinary skill in the art to practice a method of making a purified protein including a final step of UF/DF as recited in reference claim 1 for the purpose of making a high concentration “bulk drug substance” having a pH of 4-7 (e.g., as recited in dependent reference claims 14 and 18), which could serve as a starting source for downstream processing at a “drug product manufacturing site.” Moreover, the ordinarily skilled artisan would have been motivated to practice any one or more of the embodiments encompassed by reference claims 26-28 e.g., via the addition of a buffer such as “glutamate,” a saccharide such as “sucrose,” a surfactant such as “polysorbate 20,” for the purpose of stabilizing the high concentration “bulk drug substance.” Moreover, it would have been obvious to one of ordinary skill in the art to use a concentration of the buffer as recited claim 16, which overlaps the buffer concentration recited in the instant claims, and to practice the method of reference claim 1 and dependent claims thereof for the purification of, e.g., anti-DLL3 and anti-CD3 bispecific T-cell engager antibody construct as recited in claim 40. A reason one of ordinary skill in the art would have been motivated to practice the method of the reference claims and produce as anti-DLL3 and anti-CD3 bispecific T-cell engager antibody construct was because such antibodies were believed in the art to effectively treat Small cell lung cancer (SCLC) with a reasonable expectation of success as taught by Giffin et al. (J Thorac Oncol., P3.12-03, October 2018, page S971, cited herewith, see full document).
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.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 5, 7, 11, 15, 18, 21, 22, 22*, 23-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 7, 10-22, and 26 of copending Application No. 17921793 (reference application) as evidenced by Brian Kelley (mAbs 1:5, 443-452; September/October 2009, cited herewith) and further in view of Giffin et al. (J Thorac Oncol., P3.12-03, October 2018, page S971, cited herewith).
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” (see 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 (see Kelley at pages 443 and 447, last full paragraphs on each).
Reference claim 11 is drawn to the formulation of claim 1 which comprises (a) a bispecific antibody construct, (b) a saccharide, (c) a surfactant, and (d) a buffer, wherein the pH of the formulation is from about 4.8 to about 5.5, wherein the formulation comprises the bispecific antibody construct at a concentration of from about 0.1 mg/ml to about 20 mg/ml.
The ordinarily skilled artisan would be motivated to prepare a bulk drug substance having at least 10 mg/mL as a starting source for downstream processing at a “drug product manufacturing site.” Moreover, the ordinarily skilled artisan would further have been motivated to practice any one or more of the buffer, saccharide and surfactant embodiments encompassed by reference claims 2-3, 5, 7, 10, and 26 in the context of this bulk drug substance having at least 10 mg/mL since each of these embodiments would be reasonably expected to contribute to the “stable aqueous pharmaceutical formulation” of base reference claim 1.
As to making a high concentration bulk drug substance based on a DLL3xCD3 bispecific antibody construct consistent with reference claims 12-21, a reason one of ordinary skill in the art would have been motivated to do so was because such antibodies were believed in the art to effectively treat Small cell lung cancer (SCLC) with a reasonable expectation of success as taught by Giffin et al. (J Thorac Oncol., P3.12-03, October 2018, page S971, cited herewith, see full document). Note that the particular DLL3xCD3 comprising bispecific antibody constructs recited in reference claims 17-21 read on the elected SEQ ID NOs: recited in the instant claims.
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.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1, 2, 5, 7, 8, 11, 12, 15, 16, 18, 21, 22, 22*, 23-29 are 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, cited herewith) and further in view of Giffin et al. (J Thorac Oncol., P3.12-03, October 2018, page S971, cited herewith).
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” (see 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 (see Kelley at pages 443 and 447, last full paragraphs on each).
Reference claim 32 is drawn to
“A method of preparing a lyophilized formulation, the method comprising: (a) cooling a lyophilization chamber containing a liquid formulation comprising a protein,a saccharide selected from the group consisting of glucose, galactose, fructose, xylose, sucrose, lactose, maltose, trehalose, or a combination thereof, and a surfactant selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer 188, poloxamer 407, triton X-100®,polyoxyethylene, PEG 3350, PEG 4000, or a combination thereof to a temperature ranging from about -35 °C to about -50 °C to produce a frozen formulation, and holding the chamber at a temperature ranging from about -40C to about -50 °C for a time period of about 2 hours to about 24 hours; (b) heating the chamber…to produce the lyophilized formulation; wherein the liquid formulation has a pH of about 3-7 …wherein the protein is present in the liquid formulation at a concentration ranging from about 0.1 mg/mL to about 100 mg/mL.” Similarly, the method of claim 61 which also depends on claim 1 specifies that “the protein is present in the liquid formulation at a concentration ranging from about 0.5 mg/mL to about 10 mg/mL.”
It would have been obvious to one of ordinary skill in the art, and the ordinarily skilled artisan would be motivated to prepare a lyophilized bulk drug substance having at least 10 mg/mL (consistent with reference claims 32 and 61) as a starting source for downstream processing at a “drug product manufacturing site” given the knowledge in the art as exemplified by the teachings of Kelley.
Moreover, the ordinarily skilled artisan would further have been motivated to practice any one or more of the pH ranges, e.g., 3-7 or 4-6, buffer, e.g., glutamic acid, saccharide, e.g., sucrose, and surfactant, e.g., polysorbate 20, embodiments encompassed by reference claims 32, 37, 38, 41, 45, 47, 50, 52, 56 and 60 in the context of this bulk drug substance having at least 10 mg/mL since each of these embodiments would be reasonably expected to support the stability of the lyophilized formulation of base reference claim 1.
As to making a high concentration, lyophilized bulk drug substance based on a DLL3xCD3 bispecific antibody construct consistent with reference claims 28-30, a reason one of ordinary skill in the art would have been motivated to do so was because such antibodies were believed in the art to effectively treat Small cell lung cancer (SCLC) with a reasonable expectation of success as taught by Giffin et al. (J Thorac Oncol., P3.12-03, october 2018, page S971, cited herewith, see full document). Note that the particular DLL3xCD3 comprising bispecific antibody constructs recited in reference claim 30 (SEQ ID NOs: 67-77) reads on the elected SEQ ID NOs: recited in the instant claims.
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.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1, 5, 7, 11, 15, 18, 21-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 8-12, 20-22, 24, 26 and 27 of copending Application No. 18022685 (reference application) as evidenced by Brian Kelley (mAbs 1:5, 443-452; September/October 2009, cited herewith) and further in view of Giffin et al. (J Thorac Oncol., P3.12-03, October 2018, page S971, cited herewith).
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” (see 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 (see Kelley at pages 443 and 447, last full paragraphs on each).
Reference claims 12 and 20 reproduced below anticipate at least claim 1:
Reference claim 12:
A pharmaceutical formulation comprising (a) a bispecific antibody construct, (b) a saccharide, (c) a surf actant, (d) a buffer, and (e) methionine present at a molar ratio of methionine to bispecific antibody construct of about 10X to about 5000X; wherein the pH of the formulation is from about 4 to about 7, wherein the formulation comprises the bispecific antibody construct at a concentration of from about 1 mg/ml to about 20 mg/ml.
Reference claim 20:
A frozen pharmaceutical formulation comprising about 1 mg/mL to about 20 mg/mL bispecific antibody construct, sucrose, glutamic acid, polysorbate 80, and about 10 mM to about 200 mM methionine, wherein the pH of the formulation is from about 4 to about 7.
It would have been obvious to one of ordinary skill in the art, and the ordinarily skilled artisan would be motivated to prepare the formulations of reference claims 12 and 20 having about 1 mg/mL to about 20 mg/mL bispecific antibody construct as a starting source for downstream processing at a “drug product manufacturing site” given the knowledge in the art as exemplified by the teachings of Kelley.
Moreover, the ordinarily skilled artisan would further have been motivated to practice any one or more of the buffer, e.g., glutamate buffer, saccharide, e.g., sucrose, and surfactant, e.g., polysorbate 20, embodiments encompassed by reference claims 3-6 and 8-11 in the context of this bulk drug substance having about 1 mg/mL to about 20 mg/mL since each of these embodiments would be reasonably expected to support the stability of the pharmaceutical formulation of base reference claim 1.
As to making a high concentration, bulk drug substance based on a DLL3xCD3 bispecific antibody construct consistent with reference claims 27, a reason one of ordinary skill in the art would have been motivated to do so was because such antibodies were believed in the art to effectively treat Small cell lung cancer (SCLC) with a reasonable expectation of success as taught by Giffin et al. (J Thorac Oncol., P3.12-03, october 2018, page S971, cited herewith, see full document). Note that the particular DLL3xCD3 comprising bispecific antibody constructs recited in reference claim 27 (SEQ ID NO: 77) is the same as SEQ ID NO: 77 of the instant claims.
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.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
No claims are allowed.
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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