Detailed Action
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 .
Claims 1, 4, 6-8, 11-12, and 16-24 are pending.
Claims 16 and 19-22 remain withdrawn for reasons made of record in the 09/09/2024 Office Action.
Claims 2-3, 5, 9-10, and 13-15 are cancelled.
Claims 1 and 24 are amended.
Claims 1, 4, 6-8, 11-12, 17-18, and 23-24 are under examination on the merits.
Priority
This application is a CON of PCT/EP2019/074303, filed on September 12, 2019 which claims the benefit of priority to European Patent Application No. 18194145.1 filed on September 13, 2018.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
IDS
The IDS submission dated 02/18/2026 has been considered.
Withdrawn Claim Rejections
The rejections of claims 9 and 13-14 are withdrawn in light of the cancellation of the claims resulting from the 02/18/2026 claim amendments.
Maintained-Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4, 6-8, 11-12, 17-18, and 23-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2016128318 A1, hereinafter referred to as ‘Boonen et al,’ and WO2011070024 A1 (as cited on IDS dated 05/10/2022), hereinafter referred to as ‘Hoffman-La Roche’ (as cited in the office action dated 09/09/2024), as applied to claims 1, 4, 6-9, 11-12, 18, and 23-24 above, in further view of WO2003020299 A1, hereinafter referred to as Li et al (as cited in the office action dated 09/09/2024), and US20140335084 A1, hereinafter referred to as Fast et al.
Regarding claims 1, 4, 6-8, 9, 11, and 17-18, Boonen et al teaches a stable liquid pharmaceutical composition comprising either 40-80 mg/ml or 50-300 mg/ml of an antibody against CSF1R, 20-200 mM sucrose (a saccharide), 0.02-0.1 % of polysorbate 80 (a known surfactant), and 40-60 mM citrate buffer at pH 4-7 (see for example, claims 1-10 and 13 and the Detailed Description of the Invention section). Note that Boonen et al teaches and explains that there are many known buffers which may be interchangeably used such as a citrate buffer or a histidine buffer (see for example, page 5 of the Detailed Description Section) and that such a buffer may be used in the formulation at a concentration of 10mM-100mM (see for example, page 5 of the Detailed Description Section). Note further that, because the specific type of histidine buffer is not mentioned, it is presumed that any histidine buffer would function in the formulation of Boonen et al (including a histidine chloride buffer as instantly claimed in claim 24).
Note that Boonen et al further teaches that, “[t]he skilled artisan is aware of the choice of surfactants available for use the liquid formulation according to any of the embodiments of the invention such as but not limited to polysorbate 80 [or] polysorbate 20…,” (see for example, pages 4-5, the Detailed Description Section).
Given that one of ordinary skill in the art would have understood polysorbates 80 and 20 to be interchangeably usable as surfactants in the formulation of Boonen et al, one of ordinary skill in the art would have further understood that a teaching to use .01-0.1% (w/v) polysorbate 80 equates to a teaching to use .01-0.1% (w/v) polysorbate 20 given that the function of the either polysorbate in the formulation would be the same, art-recognized function possessed and performed by both equivalent surfactants and would have found it obvious to use polysorbate 20 in the formulations of Boonen et al.
Boonen et al further teaches that sucrose may be used at a concentration of 250mM (see for example, page 17 of the disclosure and Table 1). Boonen et al does not explicitly teach the antibody having the claimed sequences, but Boonen et al claim a generic anti-CSF-1R antibody (such that any anti-CSF-1R antibody would be reasonably expected to work in/be stabilized by the formulation of Boonen et al).
However, Hoffman-La Roche remedies any deficiency of Boonen et al by teaching an anti-CSF-1R antibody comprising sequences identical to the instantly claimed HCDRs1-3 (instant SEQ ID NOs: 1-3) and heavy chain variable region (instant SEQ ID NO: 7) (see for example, Hoffman-La Roche SEQ ID NO 39 at Hoffman-La Roche claim 3) as well as LCDRs1-3 (instant SEQ ID NOs: 4-6) and light chain variable region (instant SEQ ID NO: 8) (see for example, Hoffman-La Roche SEQ ID NO: 40 of Hoffman-La Roche’s claim 3). Note that the antibody of Hoffman-La Roche is taught to bind to human CSF-IR fragment delD4 (SEQ ID NO: 65) and to human CSF-IR Extracellular Domain (SEQ ID NO : 64) with a ratio of 1:50 or lower (see for example, claim 1, wherein SEQ ID NO: 64 of Hoffman-La Roche is presumed identical to instant SEQ ID NO: 12 and SEQ ID NO: 65 of Hoffman-La Roche is presumed identical to instant SEQ ID NO: 11, given that they point to the same region of CSF-1R.
Boonen et al and Hoffman-La Roche teach the limitations of claims 1 and 17, as discussed above, but do not teach the use of methionine as a second stabilizer.
However, Fast et al and Li et al teach the use of methionine as a stabilizer. Li et al teach pharmaceutical formulations comprising a biologically active agent and methionine, wherein said formulations demonstrate improved stability, and wherein said formulations do not contain human serum albumin, wherein the concentration of methionine used ranges from 0.5-50mM (see for example, the abstract and claim 2). Fast et al teach CD44 antibody formulations wherein methionine, at a concentration of 5mM-15mM (with 10mM being a preferred embodiment), may be used as a stabilizer with trehalose (see for example, paragraphs 0058-0070).
Regarding claim 12, it is noted that Boonen et al recited that trehalose was tested as stabilizer. Boonen et al do not teach trehalose as preferred, but do not teach that trehalose failed to stabilize the antibody in the formulation (see for example pg. 16, example 1). Fast et al teach trehalose in connection with methionine for stabilizing an antibody in a formulation as successful, as discussed above.
Regarding claim 23, note that Boonen et al mentions ‘sodium chloride’ three times through the entirety of the reference and notes that 21 of 110 formulations were tested with 2 stabilizers (one being sodium chloride), but that the other 89 formulations were tested a single stabilizer (wherein it is presumed not all were tested with sodium chloride as the sole stabilizer given that the reference does not ascribe any particular importance or favoritism to sodium chloride). Therefore, absent evidence to the contrary, it is presumed that the formulations of Boonen et al would have functioned without sodium chloride so as to make obvious formulations devoid of sodium chloride.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Boonen et al, Hoffman-La Roche, Li et al, and Fast et al. The artisan would have been motivated to make and use the invention as claimed because Boonen teaches formulations for stable delivery of an antibody wherein Fast et al and Li et al teach that the use of methionine as an additional stabilizer with trehalose or sucrose, as employed in the formulations of Boonen et al, further stabilizes a wide variety of proteins ranging from interleukins up to antibodies) with both sources guising to the use of 10mM methionine as preferred irrespective of the weight of the protein being stabilized.
Given that the recitation of CSF-1R antibody of Boonen is generic and the antibody generically recited in Boonen presumably performs the same function as that of the Hoffman-La Roche reference (to bind CSF-1R), one of ordinary skill in the art would have recognized the antibodies of Boonen and Hoffman-La Roche to be interchangeable biological equivalents and would have presumed the formula of Boonen et al would stabilize the antibody of Hoffman-La Roche which would perform the same function, successful binding, as the generic anti-CSF-1R antibody of Boonen et al. Note that it is prima facie obvious to swap one known equivalent for another to achieve the same purpose, here, to create an stable antibody formulation of an antibody able to bind CSF-1R (see MPEP sections 2143(I)(B) and 2144.06 (II)). Therefore, one of ordinary skill in the art would have been motivated to alter the formula of Boonen et al to comprise the antibody of Hoffman-La Roche to obtain a successfully stabilized formula of an antibody capable of binding CSF-1R in the manner claimed.
The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Here, the combination of elements known to stabilize a protein (such as an antibody) formulation would be predictably combined to achieve the same purpose of stabilizing a protein (such as an antibody) formulation.
Furthermore, Boonen et al teach and suggest the use of sucrose in the formulation at concentrations of 20-200mM or 250mM which ostensibly teaches and suggests a reasonable expectation of success using sucrose in the formulation at a concentration of 200-250mM where the concentration within this rage is understood to be a result-effective variable for routine optimization. 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 point to, for example, concentration of sucrose, this passage points to numerous variables that affect the function of inventions, such as concentration of reagents and pH ranges. Furthermore, this passage indicates that the optimization of such variables is often obvious activity for one of ordinary skill in the art. It is submitted that the claimed concentration of sucrose is akin to the variables discussed in the cited MPEP passage, because said concentrations and ranges are optimizable variables that would affect at least the efficacy and/or stability, i.e., function, of the claimed invention. 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 concentration of sucrose because such optimization would produce a more effective/stable invention. Presently, one of ordinary skill in the art would have selected to optimize the concentration of sucrose within the range of 20-250mM because Boonen et al teaches that this centration range is successful in stabilizing the formulation, as discussed above. Boonen et al additionally teaches that the buffer such as citrate (for which histidine is an art acknowledged alternative, as discussed above) may be used at a concentration of 10-100mM (see for example, page 5 of the disclosure and the Detailed Description Section).
The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Maintained-Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. Fixed above1985); 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, 4, 6-8, 11-12, 17-18, and 23-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 part C of U.S. Patent No. 11512133 (as cited in the Office Action dated 09/09/2024) in view of WO2016128318 A1, hereinafter referred to as ‘Boonen et al,’ (as cited in the Office Action dated 09/09/2024), WO2003020299 A1, hereinafter referred to as Li et al (as cited in the office action dated 09/09/2024), and US20140335084 A1, hereinafter referred to as Fast et al. Although the claims at issue are not identical, they are not patentably distinct from each other because they claim the same anti-CSF-1R antibody by claiming the same sequences.
Regarding claims 1, 4, 6-8, 11, and 17-18, Boonen et al teaches a stable liquid pharmaceutical composition comprising either 40-80 mg/ml or 50-300 mg/ml of an antibody against CSF1R, 20-200 mM sucrose (a saccharide), 0.02-0.1 % of polysorbate 80 (a known surfactant), and 40-60 mM citrate buffer at pH 4-7 (see for example, claims 1-10 and 13 and the Detailed Description of the Invention section). Note that Boonen et al teaches and explains that there are many known buffers which may be interchangeably used such as a citrate buffer or a histidine buffer (see for example, page 5 of the Detailed Description Section) and that such a buffer may be used in the formulation at a concentration of 10mM-100mM (see for example, page 5 of the Detailed Description Section). Note further that, because the specific type of histidine buffer is not mentioned, it is presumed that any histidine buffer would function in the formulation of Boonen et al (including a histidine chloride buffer as instantly claimed in claim 24).
Note that Boonen et al further teaches that, “[t]he skilled artisan is aware of the choice of surfactants available for use the liquid formulation according to any of the embodiments of the invention such as but not limited to polysorbate 80 [or] polysorbate 20…,” (see for example, pages 4-5, the Detailed Description Section).
Boonen et al further teaches that sucrose may be used at a concentration of 250mM (see for example, page 17 of the disclosure and Table 1). However, U.S. Patent No. 11512133 remedies this deficiency, teaching an anti-CSF-1R antibody comprising sequences identical to the instantly claimed HCDRs1-3 (instant SEQ ID NOs: 1-3) and heavy chain variable region (instant SEQ ID NO: 7) (see for example, U.S. Patent No. 11512133 SEQ ID NO: 39 at U.S. Patent No. 11512133 claim 1 part c) as well as LCDRs1-3 (instant SEQ ID NOs: 4-6) and light chain variable region (instant SEQ ID NO: 8) (see for example, U.S. Patent No. 11512133 SEQ ID NO: 40 at U.S. Patent No. 11512133 claim 1 part c).
Regarding claims 1 and 17, Boonen et al and U.S. Patent No. 11512133 teach the limitations of claims 1 and 17, as discussed above, but do not teach the use of methionine as a second stabilizer.
However, Fast et al and Li et al teach the use of methionine as a stabilizer. Li et al teach pharmaceutical formulations comprising a biologically active agent and methionine, wherein said formulations demonstrate improved stability, and wherein said formulations do not contain human serum albumin, wherein the concentration of methionine used ranges from 0.5-50mM (see for example, the abstract and claim 2). Fast et al teach CD44 antibody formulations wherein methionine, at a concentration of 5mM-15mM (with 10mM being a preferred embodiment), may be used as a stabilizer with trehalose (see for example, paragraphs 0058-0070).
Regarding claim 12, it is noted that Boonen et al recited that trehalose was tested as stabilizer. Boonen et al do not teach trehalose as preferred, but do not teach that trehalose failed to stabilize the antibody in the formulation (see for example pg. 16, example 1). Fast et al teach trehalose in connection with methionine for stabilizing an antibody in a formulation as successful, as discussed above.
Regarding claim 23, note that Boonen et al mentions ‘sodium chloride’ three times through the entirety of the reference and notes that 21 of 110 formulations were tested with 2 stabilizers (one being sodium chloride), but that the other 89 formulations were tested a single stabilizer (wherein it is presumed not all were tested with sodium chloride as the sole stabilizer given that the reference does not ascribe any particular importance or favoritism to sodium chloride). Therefore, absent evidence to the contrary, it is presumed that the formulations of Boonen et al would have functioned without sodium chloride so as to make obvious formulations devoid of sodium chloride.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Boonen et al, Hoffman-La Roche, Li et al, and Fast et al. The artisan would have been motivated to make and use the invention as claimed because Boonen teaches formulations for stable delivery of an antibody wherein Fast et al and Li et al teach that the use of methionine as an additional stabilizer with trehalose or sucrose, as employed in the formulations of Boonen et al, further stabilizes a wide variety of proteins ranging from interleukins up to antibodies) with both sources guising to the use of 10mM methionine as preferred irrespective of the weight of the protein being stabilized.
Given that the recitation of CSF-1R antibody of Boonen is generic and the antibody generically recited in Boonen presumably performs the same function as that of the U.S. Patent No. 11512133 reference (to bind CSF-1R), one of ordinary skill in the art would have recognized the antibodies of Boonen and U.S. Patent No. 11512133 to be interchangeable biological equivalents and would have presumed the formula of Boonen et al would stabilize the antibody of U.S. Patent No. 11512133 which would perform the same function, successful binding, as the generic anti-CSF-1R antibody of Boonen et al. Note that it is prima facie obvious to swap one known equivalent for another to achieve the same purpose, here, to create an stable antibody formulation of an antibody able to bind CSF-1R (see MPEP sections 2143(I)(B) and 2144.06 (II)).Therefore, one of ordinary skill in the art would have been motivated to alter the formula of Boonen et al to comprise the antibody of U.S. Patent No. 11512133 to obtain a successfully stabilized formula of an antibody capable of binding CSF-1R.
The MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Here, the combination of elements known to stabilize a protein (such as an antibody) formulation would be predictably combined to achieve the same purpose of stabilizing a protein (such as an antibody) formulation.
Furthermore, Boonen et al teach and suggest the use of sucrose in the formulation at concentrations of 20-200mM or 250mM which ostensibly teaches and suggests a reasonable expectation of success using sucrose in the formulation at a concentration of 200-250mM where the concentration within this rage is understood to be a result-effective variable for routine optimization. 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 point to, for example, concentration of sucrose, this passage points to numerous variables that affect the function of inventions, such as concentration of reagents and pH ranges. Furthermore, this passage indicates that the optimization of such variables is often obvious activity for one of ordinary skill in the art. It is submitted that the claimed concentration of sucrose is akin to the variables discussed in the cited MPEP passage, because said concentrations and ranges are optimizable variables that would affect at least the efficacy and/or stability, i.e., function, of the claimed invention. 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 concentration of sucrose because such optimization would produce a more effective/stable invention. Presently, one of ordinary skill in the art would have selected to optimize the concentration of sucrose within the range of 20-250mM because Boonen et al teaches that this centration range is successful in stabilizing the formulation, as discussed above. Boonen et al additionally teaches that the buffer such as citrate (for which histidine is an art acknowledged alternative, as discussed above) may be used at a concentration of 10-100mM (see for example, page 5 of the disclosure and the Detailed Description Section).
The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Applicant’s Arguments and Responses:
A. Applicant argues for withdrawal of the rejections under 35 USC §103, relying on suggested unpredictability of the formulation resulting from the combined prior art to stabilize the anti-CSF-1R antibody recited in the instant claims and for the stabilizing capacity of a formulation without NaCl (see for example, pages 5-8 of the 02/18/2026 remarks).
Response: First, Boonen et al teach a formula for stabilizing a generic anti-CSF-1R antibody. While Applicant provides an alignment showing sequential differences in the antibody instantly claimed and the antibody disclosed by Boonen et al, Applicant fails to show that these differences are relevant. If the instant claims were directed towards the antibody rather than a formulation for stabilizing the antibody (where the antibody is axillary to the claimed invention), Applicants arguments may be persuasive. However, that is not the case. Here, the claims are directed to a formulation. Applicant suggests unpredictability citing a reference teaching the propensity of antibodies to aggregate and means for designing variable domains resistant to aggregation. Applicant has not developed the discussion of Dudgeon et al beyond merely citing the reference as supporting the tendency towards aggregation. Dudgeon’s teachings are not connected to either of the instantly claimed antibody or the antibody of Boonen et al. Thus, there is no evidenced argument to distinguish the instant claims over the prior art or to support a showing of unpredictability sufficient to overcome the obviousness type rejections of record. Therefore, while the Dudgeon et al reference has been considered, it is unpersuasive at this time. Moreover, while Applicant attacks the Boonen et al reference individually, the reference is never used in isolation to reject even a single claim. Boonen et al is cited as part of a 103 rejection citing 4 total references (see In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); see also In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986)). Applicant does not discuss the combined references. Hoffman La Roche teach the antibody having the instantly recited structures and it is maintained that the combined references make obvious the instantly claimed formulation. No evidenced argument regarding the unpredictability of stabilizing a specific antibody has been developed by Applicant on the record at this time. In the absence of a developed argument to consider, the prior art is presumed enabled (see MPEP §2121(I)), absent a convincing showing to the contrary. The showing to the contrary must be evidenced on the record. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). See MPEP 2145 (I). Second, the fact that Applicant has data suggesting that inclusion of NaCl decreases the stabilizing capacity of the formulation does not address or overcome the teachings of the cited prior art references which make obvious a formulation devoid of NaCl. Boonen et al do not need to teach a particular benefit associated with omitting NaCl, the prior art references only need to make obvious a formulation free from NaCl, which they do as discussed in greater detail above. Therefore, this argument is unpersuasive. The rejections of record under 35 USC §103, reproduced above, are therefore maintained at this time.
B. Applicant does not make a specific argument related to the rejections for double patenting, but merely reiterates the assertion of unpredictability argued in greater detail in the request for withdrawal of the rejections under 35 USC §103.
Response: This argument is unpersuasive for reasons articulated in point A above. The rejections for double patenting are therefore maintained at this time.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Toprani et al (Development of a candidate stabilizing formulation for bulk storage of a double mutant heat labile toxin (dmLT) protein based adjuvant. Vaccine. 2017 Oct 4;35(41):5471-5480. doi: 10.1016/j.vaccine.2017.03.101. Epub 2017 May 24) teach that methionine may be used with polysorbate 80 to stabilize a formulation.
WO 2011029892 A2 (as cited on the 03/29/2024 IDS) relates to a highly concentrated, stable pharmaceutical formulation of a pharmaceutically active anti-CD20 antibody, such as e.g. Rituximab, Ocrelizumab or HuMab<CD20>, or a mixture of such antibody molecules for subcutaneous injection. In particular, the present invention relates to formulations comprising, in addition to a suitable amount of the anti-CD20 antibody, an effective amount of at least one hyaluronidase enzyme as a combined formulation or for use in form of a co-formulation. The said formulations comprise additionally at least one buffering agent, such as e.g. a histidine buffer, a stabilizer or a mixture of two or more stabilizers (e.g. a saccharide, such as e.g. α,α-trehalose dihydrate or sucrose, and optionally methionine as a second stabilizer), a nonionic surfactant and an effective amount of at least one hyaluronidase enzyme. Methods for preparing such formulations and their uses thereof are also provided.
WO 2014036076 A1 (as cited on the 03/29/2024 IDS) teaches an anti-PRLR antibody formulation, comprising 0 mM to 70 mM histidine, 50 ppm to 300 ppm of a non-ionic surfactant; c. 34 mM to 292 mM of a sugar selected from mannitol, dextrose, glucose, trehalose, and sucrose, 0 mM to 50 mM arginine, 0 mM to 50 mM lysine, 0 mM to 270 mM glycine or alanine, 0 mM to 10 mM methionine; and 1 mg/ml to 150 mg/ml of an anti-PRLR antibody; wherein said anti-PRLR antibody formulation has a pH ranging from pH 5.0 to pH 6.5.
WO 2016103093 A1 (as cited on the 03/29/2024 IDS) teaches an aqueous formulation comprising 50 mg/ml of an anti-Tumor Necrosis Factor alpha (TNFa) protein, or an antigen-binding fragment thereof; about 20 mM histidine buffer; about 85 mg/ml_ sucrose; about 0.2 mg/ml_ methionine; about 0.2 mg/ml polysorbate 80; about 0.05 mg/ml disodium EDTA dihydrate; and wherein the formulation has pH at 5.5.
SINGH, S.K. (2017). "Sucrose and Trehalose in Therapeutic Protein Formulations," Chapter 3 in Challenges in Protein Product Development AAPS Advances in the Pharmaceutical Sciences Series 38:63-95, 61 pages (as cited on the 12/06/2024 IDS) is held to be pertinent to selection of the saccharide in the instant Application.
US20100172862A1 teaches aqueous pharmaceutical formulations comprising an antibody, or antigen-binding portion thereof, wherein the formulation has enhanced stability, including enhanced resistance to fragmentation, wherein the formulation may comprise mannitol, polysorbate 80 and methionine wherein trehalose may be an alternative to mannitol (see for example the abstract and paragraphs 0029-0030, 0034, 0067, 0121, 0124, and 0171).
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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