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 the invention of Group I in the reply filed on 11-17-25 is acknowledged.
Applicant’s further election of:
the species of method “wherein the UF/DF filtration buffer does not comprise β-cyclodextrin, rather β-cyclodextrin is added to the filtration pool subsequent to UF/DF,” and
the species of method “wherein the first binding domain of the bispecific molecule of claim 1 binds to CD19,” and
the species of method “wherein the single sub-species of the CD19-binding domain of the first binding domain comprises the CDR sequences set out in claim 18(a),” i.e., CDR-H1 as depicted in SEQ ID NO: 4, CDR-H2 as depicted in SEQ ID NO: 5, CDR-H3 as depicted in SEQ ID NO: 6, CDR-L1 as depicted in SEQ ID NO: 1, CDR-L2 as depicted in SEQ ID NO: 2 and CDR-L3 as depicted in SEQ ID NO: 3,
is also acknowledged.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction or election species requirements, applicant’s elections have been treated as elections without traverse (MPEP § 818.01(a)).
That said, upon further consideration the species of method under examination has been extended to further include the species of method “wherein the first binding domain of the bispecific molecule of claim 1 binds to CD33,” and the species of method “wherein the single sub-species of the CD33-binding domain of the first binding domain comprises the CDR sequences set out in claim 18((b).”
Claims 1-21 are pending.
Claims 1 and 3-16, 18 and 19 are under examination as they read on:
the species of method “wherein the UF/DF filtration buffer does not comprise β-cyclodextrin, rather β-cyclodextrin is added to the filtration pool subsequent to UF/DF,” and
the species of method “wherein the first binding domain of the bispecific molecule of claim 1 binds to CD19 or CD33,” and
the species of method “wherein the single of CD19-binding domain comprises the CDR sequences set out in claim 18(a), and wherein the single of CD33-binding domain comprises the CDR sequences set out in claim 18(b).”
Claims 2, 17, 20 and 21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups or species of invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11-17-25.
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, 3-16 and 18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 and dependent claims thereof are rife with instances of a broad range or limitation followed by / paired with narrower range(s) or limitation(s) that fall within the broad range or limitation (in the same claim). Such recitations are considered indefinite because the resulting claim does not clearly set forth the metes and bounds of the patent protection desired in that there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, such recitations are explicitly set forth in claim 1, as well as in certain dependent claims such as claims 4, 5, 8-12 and 14-17.
As an example see claim 16, “The method of claim 1 comprising at least one, preferably all, of the steps of (a) providing harvested cell culture… (k) add β-cyclodextrin to the eluate of (j) within 10 hours after the end of the filtration (j) to a concentration of 0.1 to 3% (m/v) of β-cyclodextrin, preferably 1% (m/v) to obtain a β-cyclodextrin-supplemented UF/DF pool to keep the molecule in its non-aggregated, preferably essentially HMW-species-free (below 95%) form;….,” wherein such as claims recites, e.g., the broad recitation of “The method of claim 1 comprising at least one… of the steps of (a)…,” and the claim also recites “The method of claim 1 comprising…preferably all…of the steps of (a)…,” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the 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.
Claim(s) 1, 4-14 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Raum et al. (20170218078, cited herewith) in view of Kanapuram et al. (20170209571, cited on an IDS, hereinafter “Kana”).
Raum teaches the production of a bispecific single chain antibody constructs having one domain which binds a target cell surface antigen, such as binds to CD19 (“AMG 103”) or binds to CD33 (“AMG 330”), having another domain which binds an extracellular epitope of CD3ε, and further having a “Half-Life Extension Modality” (HLE), such as a “BiTE®-scFc,” wherein a BiTE is joined to a functional hinge, CH2 and CH3 domain (see, e.g., paras 1, 2, 20, 108-113, 76-81, 171, 172 and 214).
At para 303 Raum teaches, “[f]or the assessment of the quality of a pharmaceutical composition comprising an antibody construct of the invention may be analyzed e.g. by analyzing the content of soluble aggregates in a solution (HMWS per size exclusion)...."
Working Example 10 of Raum teaches "Preformulated drug substances containing purified CD33cc-hALB, CD33cc-hFc, and CD33cc-scFc respectively were buffer exchanged via ultrafiltration/diafiltration using membranes with a molecular weight cut-off (MWCO) of 10 kDa."
Given the teachings of Fig. 1A, and at paragraphs 0171-177, it further would have been obvious to the ordinarily skilled artisan that wherever Raum refers to a “CD33cc-scFc” construct it is referring to a bispecific single chain Fc antibody construct having a general structure as portrayed in Fig. 1A and having a specific structure comprising a “CD33cc-scFc” as set forth in para 214 of Raum, i.e., SEQ ID NOs: 54, 55, 60 and 61.
A comparison of Raum SEQ ID NOs: 54, 55, 60 and 61 with SEQ ID NO: 41 of the instant specification is shown below for reference:
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For example, at working Example 10 Raum describes how (emphasis added), "[p]reformulated drug substances containing purified…CD33cc-scFc…were buffer exchanged via ultrafiltration/diafiltration….Final formulation was achieved by adding concentrated stock solutions. Resulting formulations for each construct are listed in Table 19. The target protein concentration was 1.0 mg/mL,” and describes the formation of “HMWS” (“High Molecular Weight Species, a measure of the content of soluble aggregates in a solution; see Raum para 303) after various antibody stresses. For example, at para 477 Raum teaches “When formulated in K60RTrT, HMWS increased in the following order in unstressed samples: scFc<hALB<hFc. The least pronounced increase in HMWS upon freeze thaw stress was observed for the scFc-construct.” This result is evident from the data presented in Table 19 on page 64; in general the CD33cc-scFc construct exhibits the least amount of HMWS under various stressed and non-stressed conditions (see Table 19: 5 freeze/thaw cycles; 2-4 weeks at 25 / 37 C).
However, Raum does not explicitly teach the methods of claim 1 and dependent claims thereof wherein the downstream method of purifying and stabilizing a bispecific antigen-binding molecule, the construct comprising at least two domains…the method comprising providing a process fluid comprising the bispecific antigen-binding molecule, wherein the process fluid is subjected to at least one filtration step, wherein said filtration step is…ultrafiltration/diafiltration (UF/DF)… wherein said addition of β-cyclodextrin to the filtration pool is made within 24 hours after the end of said filtration step, wherein the concentration of β-cyclodextrin in the buffer applied in the filtration step or in the filtration pool is 0.1 to 3% (m/v) to keep the molecule essentially in a non-aggregated form characterized as the monomeric content of the molecule as determined preferably by size exclusion chromatography, wherein the percental monomeric peak is at least 95% after 50 hours of hold time after the end of the filtration step.
Kana teaches how recombinant protein aggregation is undesirable for many reasons, and further teaches that it can occur in many different settings / different stages of recombinant protein production and downstream processing, see paras 2-6, wherein paras 3-4 are reproduced below for reference:
“…[protein aggregation] is particularly problematic because it is encountered routinely during refolding, purification, sterilization, shipping, and storage processes. Aggregation can occur even under solution conditions where the protein native state is highly thermodynamically favored (e.g., neutral pH and 37° C.) and in the absence of stresses (Chi et al., Pharm Res, Vol. 20, No. 9, September 2003, pp. 1325-1336, Roberts, Trends Biotechnol. 2014 July; 32(7):372-80, Wang, Int J Pharm. 1999 Aug. 20; 185(2):129-88, Mahler J Pharm Sci. 2009 September; 98(9):2909-34.).
Protein aggregation is problematic because it can impair biological activity of the therapeutic proteins. Moreover, aggregation of proteins leads to undesirable aesthetics of the drug product, and decreases product yield due to elaborate purification steps that are required to remove the
aggregates from the end product. More recently, there has also been growing concern and evidence that the presence of aggregated proteins (even humanized or fully human proteins)
can significantly increase the risk that a patient will develop an immune response to the active protein monomer, resulting in the formation of neutralizing antibodies and drug resistance, or other adverse side effects (Mahler J Pharm Sci. 2009 September; 98(9):2909-34.”
Kana teaches the presence of various β-cyclodextrins, such as hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD), at concentrations “in the range of 0.1 % to 20% (w/v), preferably of 0.5% to 2% (w/v) and more preferably of 0.8% to 1.5% (w/v),….” in pharmaceutical compositions comprising bispecific single chain antibody constructs having one domain which binds a target cell surface antigen, such as CD19 (“AMG 103”) or CD33 (“AMG 330”), and further having another domain which binds an extracellular epitope of CD3ε, increases the stability of said bispecific molecules (see, e.g., paras 7, 8, 38, 77, 110, 113 and 114).
For example, with respect to a CD33 x CD3 bispecific single chain antibody constructs, at para 79 Kana teaches SEQ ID NO: 180 which is described in the Sequence Listing Table at page 37 as “"CD33-scFc BiTE anti-body con-struct CD33-_2-scFc." Note that Kana SEQ ID NO: 180 is identical to SEQ ID NO: 41 of Example 1 of the instant specification as shown below:
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Likewise, with respect to a CD19 x CD3 bispecific single chain antibody constructs,
at para 19 Kana teaches SEQ ID NO: 174 is the “AMG 103” BiTE, and it would, in turn, be obvious to one of ordinary skill in the art to join said bispecific “AMG 103” BiTE / SEQ ID NO: 174 of Kana to an scFc HLE in the same way that the CD33 x CD3 BiTE of “AMG 330” (Kana SEQ ID NO: 100 at para 15) was joined to an scFc HLE to produce Kana SEQ ID NO: 180.
The stabilizing properties of β-cyclodextrins as exemplified by reduced aggregation of bispecific antibody constructs exposed to various environmental stress factors are described, e.g., in paras 37, 45, 50 and 51. For example, para 45 of Kana describes how β-cyclodextrins like SBE-β-CD and HP-β-CD are capable of stabilizing pharmaceutical compositions of the invention by causing them to be "...free or substantially free from protein aggregates even when subjected to stress, in particular thermal stress, storage, surface induced stress (such as freeze/thaw cycles, foaming), concentration (by ultra- and diafiltration)...." (emphasis added); likewise, in para 50 Kana describes how the presence of β-cyclodextrins in the pharmaceutical composition of the invention “favor an increased colloidal stability of the bispecific single chain antibody constructs, and thus exhibit a reduced or even absent liquid-liquid phase separation (LLPS)….Pharmaceutical compositions comprising β-cyclodextrins according to the invention have been found to comprise higher concentrations of the bispecific single chain antibody construct in the LLPS protein-poor phase, as compared to pharmaceutical compositions not comprising β-cyclodextrins. Accordingly, pharmaceutical compositions of the invention are envisaged to exhibit reduced LLPS or no LLPS at all when compared to controls, and thus promoting an increased colloidal stability of the bispecific single chain antibody constructs of the present invention.”
In para 120 Kana further teaches that “Besides the β-cyclodextrin and the buffer described
previously, the pharmaceutical composition may optionally comprise one or more further excipients as long as they do not reduce or abolish its advantageous properties as described herein, and in particular its stability,” and then lists various exemplary excipients including polysorbate 80 (para 156, 164 and 168) and sucrose (paras 136, 147, 150, 155, 163, 164 and 168). Along these same lines, suitable buffering salts at various concentrations which yield certain pH values are disclosed in paras 115-117 of Kana.
Working Example 12 of Kana describes how a bispecific CD33 binding x CD3 binding antibody drug substance (“AMG 330” i.e., SEQ ID NO: 100) that was concentrated by ultrafiltration/
diafiltration (UF/DF) prior to final formulation in a composition comprising 1% SBE-β-CD (presumably w/v, see above) and wherein the bispecific is present at 1 mg/mL, did not form aggregates after storage at -20 C, -30 C and -70 C for up to 6 weeks as compared to a PEG-based AMG 330 formulation which did form aggregates when stored at -20 C (see Table 16, para 240 and Fig. 16).
Similarly, working Example 9 of Kana describes how AMG 330 formulated in the presence of various concentration of, inter alia, SBE-β-CD, 20 mM Citrate, pH 6.0, and PS80 “…appear[ed] to provide benefit toward reducing aggregation and increasing relative monomer levels during F/T [freeze/thaw] in comparison to other formulations.” (see paragraphs 216 and 222-224 (which encompasses Table 13 in its breadth); Fig. 12D).
Working Example 15 of Kana describes the purification of a CD33-scFc BiTE antibody construct via Protein A and cation exchange chromatography (CEX), wherein the CEX eluate was concentrated and the CD33-scFc BiTE antibody was formulated in a variety of buffers listed in Table 19, some of which comprise “hydroxypropyl-beta-cyclodextrin” (“HPBCD”), such as the formulations designated with “G42HP12…” and “G42HP6….”
As an aside, it should be noted that the ordinarily skilled artisan would understand a “CD33-scFc BiTE antibody construct” to refer to SEQ ID NO: 180 of Kana which is described in the Sequence Listing Table at page 37 as “"CD33-scFc BiTE anti-body con-struct CD33-_2-scFc," i.e., the ordinarily skilled artisan would assume that the CD33-scFc BiTE Antibody Construct purified and formulated with or without HPBCD in Example 15 is the SEQ ID NO: 180 construct of Kana (as shown above SEQ ID NO: 180 of Kana is the same as SEQ ID NO: 41 of the instant specification).
Paragraph 260 of working example 15 describes the method used to detect the presence of “high molecular weight species” (HMWS) in said formulations, e.g., “Vials were stored at -20 and - 70° C. Samples were pulled at designated time points. After sampling vials were thawed at ambient temperature and analyzed via size exclusion ultra-high performance chromatography (SE-UPLC) in order to quantify the percentage content of high molecular weight species.”
Paragraphs 261-262 of working example 15 describe how the presence of HPBCD ensured that the CD33-scFc BiTE did not aggregate, e.g., at -20 C for up to 12 weeks, by contrast to formulations lacking HPBCD:
[0261]…Relative area under the curve of HMWS was reported (FIG. 18).
[0262] Storage of formulated CD33-scFc BiTE antibody construct at - 70° C. or below inhibited the formation of HMWS. However, HMWS significantly increased during storage at -20° C. for formulations that did not contain HPBCD. In contrast, the protein was prevented from forming
HMWS at -20° C. in presence of HPBCD irrespective of its concentration (6 or 12%). The presence of mannitol detrimentally affected stability at -20° C. indicated by an increase in HMWS.”
It would be clear to one of ordinary skill in the art from the context of the above teachings of Kana and from Figures 18 and 19, per se, that “FIG. 18” in para 261 is a typographical error that should instead refer to “FIG. 19.” See also the descriptions of Figure 18 and 19 at paragraphs 32 and 33.
Additionally, the ability of various β-cyclodextrins such as HP-β-CD and SBE-β-CD to mitigate various other stresses to bispecific antibody formulations is disclosed in Example 1 (temperature induced stress), Example 2 (surface induced stress conditions caused by, e.g., successive freezing and thawing cycles as well as foaming effects), Examples 3 and 4 (aggregation stress caused by the anti-microbial Formulation additive benzyl alcohol), Example 5 (storage-induced stress due to six days at 37 C), Example 7 (Liquid-Liquid Phase Separation (LLPS) stress), and others (Examples 8 and 11).
Given the teachings of Raum in view of Kana it would be obvious to the ordinarily skilled artisan wishing to make CD19xCD3 HLE construct, e.g., a CD19-binding, AMG103-based x CD3-binding bispecific, or a CD33xCD3 HLE construct, e.g., a CD33-binding, AMG330-based x CD3-binding bispecific, either of said bispecific constructs comprising the scFc HLE moiety, by a process that involves a UF/DF purification + buffer exchange step that a β-cyclodextrin, such as HPBCD or SBE-β-CD, should be added to the post-UF/DF product pool in the presence of a polysorbate, such as polysorbate 80, and a sugar, such as sucrose, wherein the post-UF/DF product pool has a pH around 6.0, so as to minimize the formation of HMWS.
More particularly, given the reference teachings set forth above it would likewise have been obvious to one of ordinary skill in the art that wherein the CD19xCD3 HLE or the CD33x CD3 HLE constructs, each comprising the scFc HLE moiety, is subjected to downstream purification via ultrafiltration / diafiltration (UF/DF), the ordinarily skilled artisan would clearly understand that the post-UF/DF product pool is an appropriate stage to ensure the bispecific CD19xCD3 HLE / CD33x CD3 HLE constructs will be stable under various stressors such as freeze thaw stress (Raum Example 10), or storage at -20 C for 6 weeks (Kana Example 12), and thus this is likewise an appropriate time to ensure that stabilizing agents such as HPBCD / SBE-β-CD, polysorbate 80 and sucrose are present.
As to dependent claims 4, 5 and 8 in particular, as described above Kana teaches the final formulation product of UF/DF (i.e., the post-UF/DF product pool) comprising bispecific single chain antibody constructs can have a variety of β-CD concentrations, a variety of final antibody concentrations, and a variety of final pH values falling within the claimed ranges, e.g., 1.0% w/v SBE-β-CD, 1.0 mg/kg bispecific single chain antibody construct and a pH around 6.0.
As to dependent claims 9-11 in particular, insofar as they recite particular concentrations of polysorbate, such as polysorbate 80; a sugar, such as sucrose; and a salt, various amounts of these additional excipients falling within the claimed ranges are taught by Kana at paras 115-116 and 164.
As to dependent claim 12 in particular, which specifies certain time-frames within which the β-CD is added to the “UF/DF pool,” given the stabilizing effect of β-CD on purified bispecific single chain antibody constructs in the post UF/DF pool described by Kana above, it would have been obvious to one of ordinary skill in the art, and one of ordinary skill in the art would have been motivated to add β-CD to the UF/DF pool as soon as the UF/DF process is complete.
As to dependent claim 14 in particular, given the various teachings of Kana described above regarding the benefits of reducing formation of HMWS, which detract from the quality of a pharmaceutical composition by having a variety of unwanted effects (see e.g. Kana para 4), it would have been obvious to one of ordinary skill in the art to optimize the downstream processing of bispecific single chain antibody constructs so as to minimize the presence of HMWS in the post-UF/DF product pool. Insofar as Kana does not explicitly teach one of ordinary skill in the art should ensure the monomeric content of bispecific single chain antibody construct be, e.g., “at least 97%,” it would have been obvious to one of ordinary skill in the art to optimize the levels of buffer salt(s), of β-CD, of sugars and of polysorbates in the final formulation so as to minimize the levels of HMWS as much as possible.
In this regard, Applicant’s attention is 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 teach, for example, practicing a purification method such that the monomeric content of a bispecific single chain antibody construct will be at least 97%, this passage nonetheless points to numerous variables that affect the function of processes of making, such as the concentration of reagents and temperature ranges. Furthermore, this passage indicates that optimization of such variables is often an obvious activity for the ordinarily skilled artisan.
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.
Thus, given the teachings of Raum and Kana set forth above, it would have been prima facie obvious to one of ordinary skill in the art to optimize the downstream processing steps of a method of making a bispecific single chain antibody construct so as to produce a post-UF/DF product pool that has minimal amounts of non-monomeric final product.
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.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Raum et al. (20170218078, cited herewith) in view of Kanapuram et al. (20170209571, cited on an IDS, hereinafter “Kana”) as applied to claims 1, 4-14 and 18 above, and further in view of Wang et al. (20130336957, cited herewith).
The teachings of Raum in view of Kana as applied to claims 1, 4-14 and 18 are set forth above.
However, Raum in view of Kana fail to explicitly teach the method of claim 3 wherein “a viral filtration step” precedes the UF/DF step of claim 1.
That said, Raum teaches viral “transduction” is common method of introducing nucleic acids into a host cell (see para 230); likewise, as illustrated by Wang at paragraph 15, at paragraph 80 including Table 1, at paragraphs 84-87, at paragraphs 114-115 and at paragraphs 123-124, viral inactivation / viral filtration prior to UF/DF was a common practice in the antibody purification art.
Thus, given the teachings of Raum and Kana as set forth above, and as further modified by the teachings of Wang, it would have been obvious to one of ordinary skill in the art practicing the method of claim 1 wherein a β-cyclodextrin at 0.1 to 3% (m/v) is added to the post-UF/DF product pool that a viral filtration step should precede said UF/DF buffer exchange / purification so as to ensure “Removal of virus, if present” (see Wang at Table 1).
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.
Claim(s) 15 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Raum et al. (20170218078, cited herewith) in view of Kanapuram et al. (20170209571, cited on an IDS, hereinafter “Kana”) as applied to claims 1, 4-14 and 18 above, and further in view of Callahan et al. (WO2019199476, cited on an IDS).
The teachings of Raum in view of Kana as applied to claims 1, 4-14 and 18 are set forth above.
However, Raum in view of Kana fail to explicitly teach the method of claim 1 “…wherein the method is conducted at a temperature between 4 and 30°C….” as required by claim 15.
That said, Kana does generally teach that increased temperatures increase chemical and structural degradation of recombinant proteins, including via promotion of aggregation (see para 42); moreover, as illustrated by Callahan at para 10, ultrafiltration and diafiltration can be carried out at a temperature of about 25 °C. Thus it would have been obvious to one of ordinary skill in the art to practice the downstream purification method of claim 1 wherein ultrafiltration and diafiltration is carried out at ≤ 25 °C.
Moreover, Raum in view of Kana fail to explicitly teach the method of claim 1 “comprising at least one, preferably all, of the steps of (a) providing a harvested cell culture fluid (HCCF) as process fluid comprising the bispecific antigen-binding molecule secreted by mammalian cells;….”
That said, the general process for the “[e]fficient and economic large scale purification of proteins, e.g., therapeutic proteins including antibodies…” is taught, e.g., by Callahan at para 2 where it is described that mammalian cell culture can be used “to produce proteins of interest in appropriate media” prior to “…processes for purifying proteins include many different steps to remove impurities from the media components and host cells.” Prior to applicant’s earliest filing date it was well-known and long understood by the ordinarily skilled artisan that the phrase “providing harvested cell culture fluid (HCCF) as process fluid comprising the bispecific…” is another way of referring to the general process for the “[e]fficient and economic large scale purification of proteins, e.g., therapeutic proteins including antibodies…” as taught by Callahan para 2. Thus, at least step (a) of claim 16 would have been obvious to one of ordinary skill in the art based on their knowledge of the prior art as reflected in the teachings Callahan para 2.
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.
Claim(s) 19 is rejected under 35 U.S.C. 103 as being unpatentable over Raum et al. (20170218078, cited herewith) in view of Kanapuram et al. (20170209571, cited on an IDS, hereinafter “Kana”) as applied to claims 1, 4-14 and 18 above, and further in view of Goudar et al. (WO2019118426, cited herewith).
The teachings of Raum in view of Kana as applied to claims 1, 4-14 and 18 are set forth above.
However, Raum in view of Kana fail to explicitly teach the method of claim 1 “…wherein the method is applied to a molecule produced by an upstream continuous manufacturing method” as required by claim 19.
That said, at paras 66-67 Goudar teaches the following (emphasis added):
“[66] A continuous process for manufacturing therapeutic proteins, in particular bispecific
antibodies is herein provided. The present invention is envisaged to gear the upstream process to the specific needs of manufacturing bispecific antibodies. Said upstream process does not only contribute to increased productivity and less requirement for space in comparison to standard fed batch manufacturing solutions known in the art. Even more, the present continues manufacturing process -preferably being a continues upstream manufacturing process- is specifically adapted for bispecific antibodies and is envisaged to result in higher product quality, i.e. less aggregated bispecific antibodies in terms of higher monomer content with respect to a fed batch manufacturing. Also, the present continuous manufacturing process advantageously provides less chemical modification, less clipping, less process -related impurities than a fed-batch manufacturing process known to the skilled person. As a particular manufacturing advantage, the output over time, based on the same cell type, also referred herein to as average HCCF daily productivity, is preferably increased at least 2-fold, preferably at least 3- fold, more preferably at least 4-fold and even more preferred at least 6-fold compared to a fed batch process known to the skilled person.
[67] It was found that a particular low product concentration in the bioreactor decisively contributes to the avoidance of aggregates, i.e. to higher relative and/or absolute monomer concentrations of product. This is essential to ensure product quality and to enhance the overall economics of the process. The less aggregates are created upstream, the less non-quality product has to be removed downstream. A product concentration below 3.5 g/l is associated with less likelihood of aggregation. Product quality is even better if the maximum product concentration is kept below 1.2 g/l throughout the upstream process. Even more preferred is a product concentration below 0.5 or even 0.3 g/L. By ensuring a sufficiently high perfusion rate of 1 vvd or, preferably, at least 2 wd or higher, economical favorable production rates of preferably aggregate -free product can be achieved. This applies to all bispecific antibody
products, irrespective of being full length antibody or a non-full -length antibody such as (single chain) bispecific antibody constructs.”
Thus, given the teachings of Raum and Kana as set forth above, and as further modified by the teachings of Goudar, it would have been obvious to one of ordinary skill in the art practicing the method of claim 1 that any upstream manufacturing steps should be peformed via a continuous manufacturing method consistent with the teachings of Goudar which would be expected to make the overall production and purification of bispecific antibody constructs more efficient and cost-effective, as well as ensuring the upstream processing steps are carried out in a manner that minimizes the formation of aggregates as taught by Goudar.
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.
No claims are allowed.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644