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 .
DETAILED ACTION
Claims 37-38, 44, and 58-60 are pending in the instant application.
Claims 53-56 have been canceled.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 3/12/2026 has been entered.
Rejections Withdrawn
The rejections of claims 53-56 are moot in view of claim cancelation.
The rejections to claims 37-38, 44, and 58-60 under 35 USC §103 are withdrawn in view of claim amendment.
The rejections to claims 37-38, 44, and 58-60 under Nonstatutory Double Patenting are withdrawn in view of claim amendment.
New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112(b)
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 37-38, 44, and 58-60 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.
Regarding instant claims 37 and 59, the claims state “the formulation does the formulation does not comprise arginine or amino acids other than histidine”, but the antibody in the formulation comprises arginine and amino acids other than histidine. Thus, the claims are indefinite. Claims 38, 44, 58, and 60 are dependent on claims 37 and 59 and further contain the indefinite subject matter and thus are also rejected.
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.
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.
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.
Claims 37-38 and 58 are rejected under 35 U.S.C. 103 as being unpatentable over US 20160339100 (Harding T et al., reference of record) and further in view of US 20100196364 (Kim KJ et al., reference of record), Kang J et al. (BioProcess International 2016 14(4) 40-45, reference of record), US 20080182978 (Rosenthal A et al., reference of record), and US 20160002341 (Dix DB et al., reference of record).
Harding taught an afucosylated anti-FGFR2IIIb antibody wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 2 and the light chain comprises the amino acid sequence of SEQ ID NO: 3 (pages 1-2, paragraph 6). Harding taught treating the solid cancer tumors breast cancer and gastric cancer by administering an effective amount of the afucosylated anti-FGFR2IIIb antibody in a pharmaceutical composition with a pharmaceutically acceptable carrier (page 2, paragraph 15 and Figures 2-6). Harding taught the treatment included administering to composition to humans (page 9, paragraph 92), which would be patients. Harding taught the afucosylated anti-FGFR2IIIb antibody was expressed in cell culture at a concentration of 3.5 mg/mL (page 21, paragraph 203). Harding taught the afucosylated anti-FGFR2IIIb antibody was purified by column chromatography and ultrafiltration to concentrate the purified material, then diafiltration to exchange into formulation buffer that consisted of 20 mM histidine, 150 mM L-arginine, 0.01% polysorbate 20 and pH 6.0 (page 21, paragraph 203). Harding taught the afucosylated anti-FGFR2IIIb antibody composition comprises one or more substances that inhibit protein aggregation, including sucrose and arginine (page 20, paragraph 192). Harding taught the composition in a liquid formulation (page 21, paragraph 187). Harding taught the anti-FGFR2IIIb in a unit dosage form (page 20, paragraph 192) and in a vial (page 20, paragraph 194), which would be a single-use vial.
Harding did not teach:
1) the concentration of the formulation following ultrafiltration of the 3.5 mg/ml expressed antibody; and 2) the concentration of the sucrose used to inhibit protein aggregation in the formulation as 270 mM; but this is obvious in view of Kim, Kang, Rosenthal, and Dix.
Kim taught the FGFR2IIIb antibody GAL-FR21 strongly inhibited the growth of SNU-16 gastric tumor xenografts (page 7, paragraph 72). Kim taught HuGAL-FR21 was comprised of VH of SEQ ID NO:10 and VL of SEQ ID NO:9 (Kim claim 18). Kim taught pharmaceutical formulations contain the antibody in a physiologically acceptable carrier, optionally with excipients or stabilizers, in the form of aqueous solutions (page 5, paragraph 52). Kim taught acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed and other standard ingredients are known to those skilled in the art (Remington's Pharmaceutical Science 16.sup.th edition, Osol, A. Ed. 1980) (page 5, paragraph 52). Kim taught the antibody is typically present at a concentration of 10-50 mg/ml (page 5, paragraph 52).
Kang taught by studying commercial antibody products, they established a rich database for successful antibody formulations (page 40, middle column, second paragraph). Kang taught although every antibody is unique, the molecules are highly similar structurally (page 40, middle column, second paragraph). Kang taught lessons learned from successful examples are invaluable in developing stable and effective formulations for new antibody formulations (page 40, middle column, second paragraph). Kang taught 37 formulations that have been successfully used in commercial antibodies, with 25 as liquid formulations, with their concentration ranging from 2 mg/mL to 200 mg/mL (page 40, middle column, third paragraph). Kang taught Table 1 lists excipients used in these antibody formulations. Kang taught some commonalities can be observed: histidine is present in 35% of formulations (page 40, middle column, second bullet), sucrose was present in 30% of liquid formulations (page 40, right column, first bullet), an 80% of formulations used one of three surfactants that includes polysorbate 20 (page 40, middle column, third bullet). Kang taught formulation development wherein stage one identifies the optimal pH, stage 2 identifies stabilizing excipients, and stage 3 is an in depth evaluation of the most stabilizing buffers and excipients (page 42, left column last paragraph to right column, third bullet). Kang taught histidine has a pKa value of 6 (page 42, middle column, second to last paragraph). Kang taught in just a few weeks, researchers can develop a stable formulation for antibody product development (page 45, left column, second paragraph).
Rosenthal taught a liquid formulation used in humans consisting of 10 mg/ml antibody in an aqueous formulation of 10 mM histidine, 275 mM sucrose, 0.01% polysorbate 20, pH 6.0 (page 59, paragraph 506).
Dix taught a formulation for stabilization of an anti-Interleukin-6 receptor (IL-6R) antibody comprising of 25-100 mg/ml antibody, 10 mM histidine, 10% sucrose, 0.2% polysorbate 20, and a pH of 6.0 (Table 9). Dix taught the stability of a 25 mg/ml antibody concentration in 10 mM histidine, 10% sucrose, 0.2% polysorbate 20, and a pH of 6.0 at 5° C, which recovers 97.8% of the native antibody after 12 months (Table 10). Dix taught embodiments where the formulation has a histidine concentration of 20 mM (specification, page 4, paragraph 36), a sucrose concentration of about 9%, which is about 262 mM sucrose (specification, page 4, paragraph 38), and a polysorbate 20 surfactant concentration of 0.01% (specification, page 4, paragraph 40) in a liquid solution (specification, page 9, paragraph 63).
Regarding instant claims 37-38 and 58, it would have been obvious for a person having ordinary skill in the art to take the pharmaceutical composition administered for the treatment of a solid cancer tumor comprising the afucosylated anti-FGFR2IIIb antibody of Harding wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 2 and the light chain comprises the amino acid sequence of SEQ ID NO: 3 in the liquid formulation buffer consisting of 20 mM histidine, 150 mM L-arginine, 0.01% polysorbate 20 and pH 6.0 – and 1) include the anti-FGFR2IIIb antibody at a concentration of 10-50 mg/ml as taught by Kim, which overlaps with 20 mg/ml; 2) exchange the arginine with sucrose as taught by Harding; 3) identify the optimal sucrose of the formulation as taught by Kang; 4) use a concentration of about 270 mM sucrose for the liquid formulation wherein no arginine or other amino acids other than histidine were in the formulation as taught by Rosenthal; and 5) expect the histidine, sucrose, polysorbate 20, pH 6.0 solution would be stable as taught by Dix.
This is obvious because:
1) Kim taught the antibody at a concentration of 10-50 mg/ml, which overlaps with 20 mg/ml, and the anti-FGFR2IIIb antibody of Harding, Kim and the instant application have 100% sequence identity (see alignment below);
VH alignment
PNG
media_image1.png
559
664
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Greyscale
VL alignment
PNG
media_image2.png
285
668
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Greyscale
2) Harding taught the afucosylated anti-FGFR2IIIb antibody composition comprises one or more substances that inhibit protein aggregation, including sucrose;
3-5) Kang taught formulation development wherein stage one identifies the optimal pH, stage 2 identifies stabilizing excipients, and stage 3 is an in depth evaluation of the most stabilizing buffers and excipients. The concentration range of sucrose tested would include 270 mM in view of concentrations in this range known to be effective in view of Rosenthal and Dix;
4) the antibody formulation of Rosenthal with 275 mM sucrose has been used in humans and a sucrose concentration within this range would be acceptable wherein no arginine or other amino acids other than histidine were in the formulation; and
5) Dix taught an antibody was stable in a liquid formulation of histidine, sucrose, polysorbate 20, at pH of 6.0, wherein the liquid formulation recovers about 98% of the native antibody after 12 months at 5°C.
There is a reasonable expectation of success because:
1)-2) the anti-FGFR2IIIb antibody of Harding, Kim and the instant application have 100% sequence identity. Further, Harding identified sucrose as an appropriate excipient to prevent aggregation and Kim recognized that the antibody formulations comprising acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed and other standard ingredients are known to those skilled in the art. Thus, thus utilizing known pharmaceutical reagents to produce stable formulations of known antibodies would further be routinely optimized and the results would affect the formulation within an expected range;
3) Kang recognized that the antibody formulations comprising acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed and other standard ingredients are known to those skilled in the art. Further, Kang taught it is common for commercial antibodies to have a formulation with histidine, sucrose, and a surfactant as polysorbate 20 and that histidine has a pKa of 6. Additionally, concentrations in the range of 270 mM are known to be effective and thus this concentration would be reasonable;
4) a formulation containing about 270 mM sucrose has been previously used in a liquid antibody formulation for humans in an aqueous formulation consisting of histidine, sucrose, polysorbate 20, pH 6.0, wherein no arginine or other amino acids other than histidine were in the formulation;
5) Dix taught an antibody was stable in a liquid formulation of histidine, sucrose, polysorbate 20, at pH of 6.0 at 5°C for 12 months.
This would produce a liquid pharmaceutical composition for a method of treating a solid cancer tumor comprising administering to a human patient (instant claim 58) an effective amount of a liquid composition consisting of:
10-50 mg/ml of an afucosylated anti-FGFR2IIIb antibody, which overlaps with 20 mg/ml;
20 mM histidine, which is a buffer;
270 mM sucrose;
0.01% polysorbate 20; and
pH 6.0,
wherein the heavy chain comprises Harding SEQ ID NO: 2 and the light chain comprises Harding SEQ ID NO: 3, which is identical to the heavy and light chain of instant SEQ ID NO:2 for VH and SEQ ID NO:3 for VL (instant claim 37), wherein no arginine or other amino acids other than histidine are in the formulation except the amino acids that comprise the antibody, wherein the pharmaceutical formulation is a liquid not for lyophilization prior to administration to a patient (instant claim 38), wherein the antibody lacks fucose at Asn297 because it is afucosylated, and wherein the protein aggregation of the formulation would naturally increase by no more than 2.0% after 6 months of storage at 5°C.
Response to Arguments
Applicant argues each of independent claims 37 and 59, as amended, recites a pharmaceutical formulation "consisting essentially of' 20 mg/mL of an anti-FGFR2 antibody comprising heavy and light chain sequences of SEQ ID NO: 2 and SEQ ID NO: 3, respectively, 20 mM of a histidine buffer, 270 mM sucrose, and 0.01 % polysorbate 20, wherein: the formulation has a pH of 6.0, the formulation does not comprise arginine or amino acids other than histidine; and protein aggregation in the formulation increases by no more than 2.0% after 6 months of storage at 5°C.
Under MPEP § 2111.03(111), the transitional phrase "consisting essentially of' limits the scope of a claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention. PPG Industries v. Guardian Industries, 156 F.3d 1351, 1354, 48 USPQ2d 1351, 1353-54 (Fed. Cir. 1998). None of the cited references, alone or in combination, teaches or suggests a formulation "consisting essentially of' 20 mg/mL of the recited anti-FGFR2 antibody and combination of excipients, let alone a formulation in which protein aggregation increases by no more than 2.0% after 6 months of storage at 5°C.
Applicant argues the Office Action has not established a reason for making the purported combination of individual elements. Applicant argues to arrive at the presently claimed formulation based on the cited references, a skilled artisan would need to make a number of specific decisions in specific relation to each other. The Office Action's allegation that various elements of the claims existed in isolation is insufficient to render the combination prima facie obvious. Rather, the MPEP makes it clear that in order to avoid improper hindsight, the Office must clearly articulate a rationale for why a skilled artisan would have made the claimed combination, at the priority date, in view of the prior art ("Rejections on obviousness cannot be sustained by mere conclusory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness." MPEP 2141 (III), quoting the Supreme Court's decision in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007)).
For example, even assuming for the sake of argument that the various isolated disclosures asserted by the Office Action were known, the skilled artisan would at least have had to decide to: (1) select an anti-FGFR2 antibody comprising heavy and light chain sequences of SEQ ID NO: 2 and SEQ ID NO: 3, respectively; (2) select an antibody concentration of 20 mg/mL from long list of possible concentrations taught by Kim; (3) eliminate the 150 mM arginine as taught by Harding; (4) include sucrose, histidine, and polysorbate 20 at concentrations of 270 mM, 20 mM, and 0.01 %, respectively, based on formulations containing irrelevant antibodies as taught by Rosenthal and Dix; and (5) exclude other amino acids, such that protein aggregation in the formulation increases by no more than 2.0% after 6 months of storage at 5°C. There is nothing in the cited references that would have prompted a skilled artisan to modify the references in the manner required to arrive at the particular claimed combination.
Further demonstrating that the proposed combination is not prima facie obvious, the Office Action has not established a reasonable expectation of success for the proposed combination (See MPEP 2143.02). The Office Action at p. 11 has made several conclusory statements that there would be a reasonable expectation of success for the alleged combination. However, when the cited art is correctly read as a whole, the evidence of record does not support, but rather refutes, the Office Action's conclusions. For example, Kang, cited by the Office Action for the rejection, expressly discloses that it was widely acknowledged in the art that each biotherapeutic molecule presents unique formulation challenges, and that formulation
development "must be case by case":
Although some or all of those sugars work as excellent stabilizers for given
modalities, it is widely acknowledged that because each biotherapeutic presents
unique formulation challenges, formulation development must be case by case.
Kang et al. MPEP 2143.02 requires the Office Action to consider the cited art as a whole, rather than individual statements in isolation. Accordingly, a reasonable expectation of success is not established by Kang' s isolated mention that antibodies may have some similar structural features (See Office Action at p. 5), because when Kang is read as a whole, it is clear that even acknowledging that antibodies can have some similar structural features, formulation development is considered to be molecule dependent, and case-by case. Thus, Applicant argues the rejection continues to rely on improper hindsight reconstruction.Applicant argues the Office Action's comparison of the unexpected results to an alleged "Harding Formulation" is improper because it is a comparison to a hypothetical combination rather than the prior art.
Additionally, the Office Action compares the claimed formulation stability to a purported "Harding formulation" comprising 20 mM histidine, 150 mM arginine, and 0.01% polysorbate 20 at pH 6.0. However, Harding does not disclose such a 20 mg/mL formulation (and the Office Action acknowledges Harding does not teach the concentration following ultrafiltration of the 3.5 mg/mL expressed antibody on page 4 of the Office Action). Accordingly, the "Harding formulation" allegedly used as a comparator is not a formulation disclosed in the prior art but rather a reconstructed, hypothetical composition.
MPEP § 716.02(e)(III) states that "applicant is not required to compare the claimed invention with subject matter that does not exist in the prior art." In In re Chapman, 357 F.2d 418, 148 USPQ 711 (CCPA 1966), the court held that requiring applicant to compare the claimed invention with a combination suggested by the references relied upon in the rejection "would be requiring comparison of the results of the invention with the results of the invention." 357 F.2d at 422, 148 USPQ at 714. Thus, the Office Action's comparison of the claimed formulation (with 20 mg/mL antibody) to a hypothetical "Harding formulation" that does not actually exist in the prior art is improper.
In response, Applicant's arguments filed 3/12/2026 have been fully considered but they are not persuasive. The updated rejection is above.
Regarding the Office Action Has Not Articulated Any Reason Why The Skilled Artisan Would Have Made The Proposed Combination, the obvious rational is above. Further, Harding taught the afucosylated anti-FGFR2IIIb antibody was purified by column chromatography and ultrafiltration to concentrate the purified material, then diafiltration to exchange into formulation buffer of 20 mM histidine, 150 mM L-arginine, 0.01% polysorbate 20 and pH 6.0 (page 21, paragraph 203). Harding further taught the afucosylated anti-FGFR2IIIb antibody composition comprises one or more substances that inhibit protein aggregation, including sucrose (page 20, paragraph 192). Thus, exchanging sucrose was taught by Harding for preventing aggregation. Further, using the prior art knowledge that a formulation containing about 270 mM sucrose in a liquid antibody formulation for humans in an aqueous formulation of histidine, sucrose, polysorbate 20, pH 6.0 would give a person having ordinary skill in the art a reasonable range for sucrose. Additionally, Dix taught an antibody was stable in a formulation of histidine, sucrose, polysorbate 20, at pH of 6.0. Thus, exchange of arginine for sucrose in the buffer is obvious with a reasonable expectation of success. Kang further taught formulation development in within the skill of a person having ordinary skill in the art, wherein stage one identifies the optimal pH, stage 2 identifies stabilizing excipients, and stage 3 is an in depth evaluation of the most stabilizing buffers and excipients. Kang taught observation of aggregation for formulation development (Kang Fig. 5). Thus, Kang taught observation of the formulation for aggregation and the sucrose concentration would be aid in suppression of the aggregation. Further, concentration of 3.5 mg/ml taught by Harding to 20 mg/ml would be reasonable in view of Dix as well, wherein 25 mg/ml is stable in a histidine, sucrose, polysorbate 20 formulation of pH 6.0. Thus, the buffer components and concentrations are within expected ranges and within the skill of a person having ordinary skill in the art as taught by Harding, Kim, Kang, Rosenthal, and Dix as described in the obvious rational above, wherein the protein aggregation of the formulation would naturally increase by no more than 2.0% after 6 months of storage at 5°C..
Regarding hindsight reasoning and there is nothing in the cited references that would have prompted a skilled artisan to modify the references in the manner required to arrive at the particular claimed combination:
It is not hindsight reasoning to exchange arginine for sucrose as taught by Harding and to use concentrations within the range of known effective antibody formulations of Rosenthal and Dix and the teaching of Kang for optimization. Further, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Regarding Kang and each biotherapeutic molecule presents unique formulation challenges, and that formulation development "must be case by case", Kang taught
although every antibody is unique, the molecules are highly similar structurally (page 40, middle column, second paragraph). Kang taught lessons learned from successful examples are invaluable in developing stable and effective formulations for new antibody formulations (page 40, middle column, second paragraph). Kang taught formulation development wherein stage one identifies the optimal pH, stage 2 identifies stabilizing excipients, and stage 3 is an in depth evaluation of the most stabilizing buffers and excipients (page 42, left column last paragraph to right column, third bullet). Kang taught in just a few weeks, researchers can develop a stable formulation for antibody product development (page 45, left column, second paragraph). Thus, Kang, the art cited above, and the obvious rational complies with MPEP 2143.02 and considers the cited art as a whole to determine the formulation above is obvious with a reasonable expectation of success.
Regarding comparison of the unexpected results to an alleged "Harding Formulation" is improper because it is a comparison to a hypothetical combination rather than the prior art:
The instant specification compares (A) 20 mM histidine, 150 mM arginine, 0.01 % polysorbate 20 ("histidine/arginine formulation"), and (B) 20 mM histidine, 150 mM sucrose, 0.01% polysorbate 20 ("histidine/sucrose formulation") (page 62, [0212]). The buffer formulation of (A) from the instant specification is identical to Harding’s buffer formulation of 20 mM histidine, 150 mM L-arginine, 0.01% polysorbate 20 and pH 6.0 (page 21, paragraph 203).
When comparing instant Fig. 23A-C (Arg formulation) and Fig. 25A-C (Suc formulation) the aggregation percentages are not unexpected. See the values below:
Arg formulation
Fig. 23A – pH 6: 3% aggregate 1 month 40°C
Fig. 23B – pH 6: ~2% aggregate 3 month 25°C
Fig. 23C – pH 6: 1.5% aggregate 6 month 5°C
Suc formulation
Fig. 25A – pH 6: 3% aggregate 1 month 40°C
Fig. 25B – pH 6: ~2% aggregate 3 month 25°C
Fig. 25C – pH 6: 1.5% aggregate 6 month 5°C
When comparing instant Fig. 24A-C (Arg formulation) and Fig. 26A-C (Suc formulation) the aggregation percentages are slightly increased and worse in the sucrose comprising formulation, which is not unexpectedly better for storage. See the values below:
Arg formulation
Fig. 24A – pH 6: 1% clip 1 month 40°C
Fig. 24B – pH 6: 1% clip 3 month 25°C
Fig. 24C – pH 6: 0.5% clip 6 month 5°C
Suc formulation
Fig. 26A – pH 6: ~1.5% clip 1 month 40°C
Fig. 26B – pH 6: 2.5% clip 3 month 25°C
Fig. 26C – pH 6: ~1% clip 6 month 5°C
The same pattern can be seen for the acidic and basic variants when comparing Fig 27A-C and Fig. 28A-C for acidic variants and 29A-C and Fig. 30A-C for acidic variants. Further in the instant specification, when comparing (i) 20 mM Histidine, 150 mM Arginine, 0.01% PS20; and (ii) 20 mM Histidine, 270 mM Sucrose, 0.01% PS20 (page 60, [0206]): mechanical agitation (page 61, Table 10) and freeze thaw stability (page 61, Table 11) were not surprising different.
Thus, the sucrose comprising formulation does not have surprising results because it possesses similar antibody storage capabilities to the arginine comprising formulation – wherein the tested arginine formulation is identical to the known Harding buffer formulation, wherein the buffer is 20 mM histidine, 150 mM L-arginine, 0.01% polysorbate 20 and pH 6.0. While Harding is silent to the antibody concentration following ultrafiltration and concentration, the initial concentration was 3.5 mg/ml and concentrations of 10-50 mg/ml were taught by Kim above. Thus, while MPEP § 716.02(e)(III) states that "applicant is not required to compare the claimed invention with subject matter that does not exist in the prior art", the claimed sucrose formulation is not surprising when compared to the arginine formulation.
Claims 37-38, 44, and 58-60 under 35 U.S.C. 103 are rejected as being unpatentable over US 20160339100 (Harding T et al., reference of record) and further in view of US 20100196364 (Kim KJ et al., reference of record), Kang J et al. (BioProcess International 2016 14(4) 40-45, reference of record), US 20080182978 (Rosenthal A et al., reference of record), and US 20160002341 (Dix DB et al., reference of record) as applied to claims 37-38 and 58 above, and further in view of Britannica (https://web.archive.org/web/20180926000417/https://www.britannica.com/science/amino-acid, Web Archive 9/26/2018 reference of record).
Harding, Kim, Kang, Rosenthal, and Dix are described above.
Harding is silent to the enantiomeric form of histidine, but this is obvious in view of Britannica.
Britannica taught all the amino acids are chiral molecules with the exception of glycine, wherein one enantiomer is designated D and the other L (page 3, Chirality, first paragraph). Reflecting the near universality of the L enantiomer, the prefix L is usually omitted (page 3, Chirality, first paragraph).
Regarding instant claims 44 and 59-60, it would have been obvious for a person having ordinary skill in the art to take the pharmaceutical composition administered for the treatment of a solid cancer tumor of Harding, Kim, Kang, Rosenthal, and Dix above – and to use the L enantiomer of the histidine buffer because Britannica taught reflecting the near universality of the L enantiomer, the prefix L is usually omitted.
There is a reasonable expectation of success because Britannica taught reflecting the near universality of the L enantiomer, the prefix L is usually omitted. Thus, the L-form of the histidine buffer is what was most likely used in the antibody formulations of Harding, Kang, Rosenthal, and Dix.
This would produce a liquid pharmaceutical composition for a method of treating a solid cancer tumor (instant claim 60) comprising administering to a human patient an effective amount of a composition consisting of:
10-50 mg/ml of an afucosylated anti-FGFR2IIIb antibody, which overlaps with 20 mg/ml;
20 mM L-histidine, which is a buffer (instant claims 44 and 59);
270 mM sucrose;
0.01% polysorbate 20;
pH 6.0,
wherein the heavy chain comprises Harding SEQ ID NO: 2 and the light chain comprises Harding SEQ ID NO: 3, which is identical to the heavy and light chain of instant SEQ ID NO:2 for VH and SEQ ID NO:3 for VL, wherein the pharmaceutical formulation consists of anti-FGFR2IIIb antibody, histidine buffer, sucrose and polysorbate 20, wherein no arginine or other amino acids other than histidine are in the formulation except the amino acids that comprise the antibody, wherein the pharmaceutical formulation is a liquid and not for lyophilization prior to administration to a patient, wherein the antibody lacks fucose at Asn297 because it is afucosylated, and wherein the protein aggregation of the formulation would naturally increase by no more than 2.0% after 6 months of storage at 5°C.
Response to Arguments
The updated rejection is above. Applicant arguments regarding unexpected results and Harding, Kim, Kang, Rosenthal, and Dix are discussed above.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 37-38 and 58 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-59 of U.S. Patent No. 11,235,059 (Harding T et al.) in view of US 20160339100 (Harding T et al., reference of record), US 20100196364 (Kim KJ et al., reference of record), Kang J et al. (BioProcess International 2016 14(4) 40-45, reference of record), US 20080182978 (Rosenthal A et al., reference of record), and US 20160002341 (Dix DB et al., reference of record).
‘059 claim 25 taught a composition which can be used for treating solid tumors, comprising an afucosylated anti-FGFR2IIIb antibody, wherein the heavy chain comprises HVR-H1-H3 of SEQ ID NO: 6-8 and the light chain variable region comprises HVR-L1-L3 of SEQ ID NO: 9-11, and further the heavy chain and light chain was taught to comprise SEQ ID NO:2 and SEQ ID NO:3 respectively in ’059 claim 31. ‘059 claim 47 taught a pharmaceutical composition comprising the afucosylated anti-FGFR2IIIb antibody of claim 25 and at least one pharmaceutically acceptable carrier.
‘059 claims 26-30, 32-38, 49, and 51 taught further details of the afucosylated anti-FGFR2IIIb antibody. ‘059 claims 39-46 taught functions of the afucosylated anti-FGFR2IIIb antibody. ‘059 claims 52 taught another afucosylated anti-FGFR2IIIb antibody. ‘059 claim 1 taught a composition which can be used for treating solid tumors, comprising an anti-FGFR2IIIb antibody, wherein the heavy chain comprises HVR-H1-H3 of SEQ ID NO: 6-8 and the light chain variable region comprises HVR-L1-L3 of SEQ ID NO: 9-11; wherein at least 95% of the anti-FGFR2IIIb antibodies in the composition are afucosylated. ‘059 claims 2-13, 23, 48, and 50 taught further details of the afucosylated anti-FGFR2IIIb antibody. ‘059 claims 14-22 taught functions of the afucosylated anti-FGFR2IIIb antibody. ‘059 claim 24 taught a pharmaceutical composition comprising the composition of the afucosylated anti-FGFR2IIIb antibody and at least one pharmaceutically acceptable carrier. ‘059 claim 25 taught
While the claims of ‘059 teach a pharmaceutical composition comprising the afucosylated anti-FGFR2IIIb antibody which can be used for treating solid tumors, ‘059 does not teach: 1) the specific buffer components and concentrations of the formulation; 2) wherein the composition is contained within in a unit dose single-use vial; and 3) wherein the pharmaceutical formulation is not for lyophilization prior to administration to a patient, but this is obvious in view of ‘100 Harding and Kim.
‘100 Harding taught an afucosylated anti-FGFR2IIIb antibody wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 2 and the light chain comprises the amino acid sequence of SEQ ID NO: 3 (pages 1-2, paragraph 6). ‘100 Harding taught treating the solid cancer tumors breast cancer and gastric cancer by administering an effective amount of the afucosylated anti-FGFR2IIIb antibody in a pharmaceutical composition with a pharmaceutically acceptable carrier (page 2, paragraph 15 and Figures 2-6). ‘100 Harding taught treatment included administering to humans (page 9, paragraph 92), which would be patients. ‘100 Harding taught the afucosylated anti-FGFR2IIIb antibody was expressed in cell culture at a concentration of 3.5 mg/mL (page 21, paragraph 203). ‘100 Harding taught the afucosylated anti-FGFR2IIIb antibody was purified by column chromatography and ultrafiltration to concentrate the purified material, then diafiltration to exchange into formulation buffer of 20 mM histidine, 150 mM L-arginine, 0.01% polysorbate 20 and pH 6.0 (page 21, paragraph 203). ‘100 Harding taught liquid formulation (page 21, paragraph 187). ‘100 Harding taught the anti-FGFR2IIIb in a unit dosage form (page 20, paragraph 192) and in a vial (page 20, paragraph 194), which would be a single-use vial.
Kim taught the FGFR2IIIb antibody GAL-FR21 strongly inhibited the growth of SNU-16 gastric tumor xenografts (page 7, paragraph 72). Kim taught HuGAL-FR21 was comprised of VH of SEQ ID NO:10 and VL of SEQ ID NO:9 (Kim claim 18). Kim taught pharmaceutical formulations contain the antibody in a physiologically acceptable carrier, optionally with excipients or stabilizers, in the form of aqueous solutions (page 5, paragraph 52). Kim taught acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed and other standard ingredients are known to those skilled in the art (Remington's Pharmaceutical Science 16.sup.th edition, Osol, A. Ed. 1980) (page 5, paragraph 52). Kim taught the antibody is typically present at a concentration of 10-50 mg/ml (page 5, paragraph 52).
Kang taught by studying commercial antibody products, they established a rich database for successful antibody formulations (page 40, middle column, second paragraph). Kang taught although every antibody is unique, the molecules are highly similar structurally (page 40, middle column, second paragraph). Kang taught lessons learned from successful examples are invaluable in developing stable and effective formulations for new antibody formulations (page 40, middle column, second paragraph). Kang taught 37 formulations that have been successfully used in commercial antibodies, with 25 as liquid formulations, with their concentration ranging from 2 mg/mL to 200 mg/mL (page 40, middle column, third paragraph). Kang taught Table 1 lists excipients used in these antibody formulations. Kang taught some commonalities can be observed: histidine is present in 35% of formulations (page 40, middle column, second bullet), sucrose was present in 30% of liquid formulations (page 40, right column, first bullet), an 80% of formulations used one of three surfactants that includes polysorbate 20 (page 40, middle column, third bullet). Kang taught formulation development wherein stage one identifies the optimal pH, stage 2 identifies stabilizing excipients, and stage 3 is an in depth evaluation of the most stabilizing buffers and excipients (page 42, left column last paragraph to right column, third bullet). Kang taught histidine has a pKa value of 6 (page 42, middle column, second to last paragraph). Kang taught in just a few weeks, researchers can develop a stable formulation for antibody product development (page 45, left column, second paragraph).
Rosenthal taught a liquid formulation used in humans consisting of 10 mg/ml antibody in an aqueous formulation of 10 mM histidine, 275 mM sucrose, 0.01% polysorbate 20, pH 6.0 (page 59, paragraph 506).
Dix taught a formulation for stabilization of an anti-Interleukin-6 receptor (IL-6R) antibody comprising of 25-100 mg/ml antibody, 10 mM histidine, 10% sucrose, 0.2% polysorbate 20, and a pH of 6.0 (Table 9). Dix taught the stability of a 25 mg/ml antibody concentration in 10 mM histidine, 10% sucrose, 0.2% polysorbate 20, and a pH of 6.0 at 5° C, which recovers 97.8% of the native antibody after 12 months (Table 10). Dix taught embodiments where the formulation has a histidine concentration of 20 mM (specification, page 4, paragraph 36), a sucrose concentration of about 9%, which is about 262 mM sucrose (specification, page 4, paragraph 38), and a polysorbate 20 surfactant concentration of 0.01% (specification, page 4, paragraph 40) in a liquid solution (specification, page 9, paragraph 63).
Regarding instant claims 37-38 and 58, it would have been obvious for a person having ordinary skill in the art to take the general pharmaceutical composition formula of ‘059 claim 47 for the treatment of a solid tumor comprising the afucosylated anti-FGFR2IIIb antibody of ‘056 claims 25 and 31 wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 2 and the light chain comprises the amino acid sequence of SEQ ID NO: 3 – and 1) include the anti-FGFR2IIIb antibody at a concentration of 10-50 mg/ml as taught by Kim, which overlaps with 20 mg/ml; 2) exchange the arginine with sucrose as taught by Harding ‘100; 3) identify the optimal sucrose of a formulations taught by Kang; 4) use a concentration of about 270 mM sucrose for the liquid formulation as taught by Rosenthal; and 5) expect the histidine, sucrose, polysorbate 20, pH 6.0 solution would be stable as taught by Dix; and 6) not lyophilize the pharmaceutical formulation as taught by Harding ‘100.
This is obvious because the afucosylated anti-FGFR2IIIb antibody of ‘056, ‘100 Harding, Kim and the instant application have 100% sequence identity; and 1) Kim taught the antibody at a concentration of 10-50 mg/ml, which overlaps with 20 mg/ml, and the anti-FGFR2IIIb antibody of Harding, Kim and the instant application have 100% sequence identity;
2) Harding taught the afucosylated anti-FGFR2IIIb antibody composition comprises one or more substances that inhibit protein aggregation, including sucrose;
3) Kang taught formulation development wherein stage one identifies the optimal pH, stage 2 identifies stabilizing excipients, and stage 3 is an in depth evaluation of the most stabilizing buffers and excipients. The concentration range of sucrose tested would include 270 mM in view of concentrations in this range known to be effective in view of Rosenthal and Dix;
4) the antibody formulation of Rosenthal with 275 mM sucrose has been used in humans and a sucrose concentration within this range would be acceptable;
5) Dix taught an antibody was stable in a liquid formulation of histidine, sucrose, polysorbate 20, at pH of 6.0, wherein the liquid formulation recovers about 98% of the native antibody after 12 months at 5°C; and
6) ‘100 Harding taught the formulation in liquid form.
There is a reasonable expectation of success because the anti-FGFR2IIIb antibody of ‘056, ‘100 Harding, Kim and the instant application have 100% sequence identity and:
1-2) ‘100 Harding taught cell culture antibody concentrations of 3 mg/ml could be concentrated in this formulation buffer. Further, Harding identified sucrose as an appropriate excipient to prevent aggregation and Kim recognized that the antibody formulations comprising acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed and other standard ingredients are known to those skilled in the art. Thus, thus utilizing known pharmaceutical reagents to produce stable formulations of known antibodies would further be routinely optimized and the results would affect the formulation within an expected range;
3) Kang recognized that the antibody formulations comprising acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed and other standard ingredients are known to those skilled in the art. Further, Kang taught it is common for commercial antibodies to have a formulation with histidine, sucrose, and a surfactant as polysorbate 20 and that histidine has a pKa of 6. Additionally, concentrations in the range of 270 mM are known to be effective and thus this concentration would be reasonable;
4) a formulation containing about 270 mM sucrose has been previously used in a liquid antibody formulation for humans in an aqueous formulation of histidine, sucrose, polysorbate 20, pH 6.0;
5) Dix taught an antibody was stable in a liquid formulation of histidine, sucrose, polysorbate 20, at pH of 6.0 at 5°C for 12 months; and
6) ‘100 Harding taught the formulation in liquid form in formulation buffer.
This would produce a liquid pharmaceutical composition for a method of treating a solid cancer tumor comprising administering to a human patient (instant claim 58) an effective amount of a composition consisting of:
10-50 mg/ml of an afucosylated anti-FGFR2IIIb antibody, which overlaps with 20 mg/ml;
20 mM histidine, which is a buffer;
270 mM sucrose;
0.01% polysorbate 20;
pH 6.0,
wherein the heavy chain comprises Harding SEQ ID NO: 2 and the light chain comprises Harding SEQ ID NO: 3, which is identical to the heavy and light chain of instant SEQ ID NO:2 for VH and SEQ ID NO:3 for VL (instant claim 37), wherein no arginine or other amino acids other than histidine are in the formulation except the amino acids that comprise the antibody, wherein the pharmaceutical formulation is a liquid not for lyophilization prior to administration to a patient (instant claim 38), wherein the antibody lacks fucose at Asn297 because it is afucosylated, wherein the protein aggregation of the formulation would naturally increase by no more than 2.0% after 6 months of storage at 5°C.
Response to Arguments
Applicant argues For at least the reasons discussed above regarding the Section 103 rejection, claims 37, 38, 44, 53-56, and 58-60 are not obvious over, and are patentably distinct from, the claims of Harding '059, whether considered alone or in any combination with Harding, King, Kang, Rosenthal, Dix, or Britannica. Accordingly, Applicant respectfully requests withdrawal of the obviousness-type double patenting rejections.
In response, Applicant's arguments filed 3/12/2026 have been fully considered but they are not persuasive. The updated rejection is above. Applicant arguments regarding unexpected results and Harding, Kim, Kang, Rosenthal, and Dix are discussed above.
Claims 37-38, 44, and 58-60 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-59 of U.S. Patent No. 11,235,059 (Harding T et al.) in view of US 20160339100 (Harding T et al., reference of record), US 20100196364 (Kim KJ et al., reference of record), Kang J et al. (BioProcess International 2016 14(4) 40-45, reference of record), US 20080182978 (Rosenthal A et al., reference of record), US 20160002341 (Dix DB et al., reference of record) and Britannica (https://web.archive.org/web/20180926000417/https://www.britannica.com/science/amino-acid, Web Archive 9/26/2018 reference of record).
The claims of the ‘059 patent in view of Harding, Kim, Kang, Rosenthal, and Dix teach the limitations of claims 37-38 and 58 for the reasons set forth above.
‘059, ‘100 Harding, Kim, Kang, Rosenthal, and Dix are described above.
‘059 is silent to the enantiomeric form of histidine, but this is obvious in view of Britannica.
Britannica taught all the amino acids are chiral molecules, wherein one enantiomer is designated D and the other L (page 3, Chirality, first paragraph). Reflecting the near universality of the L enantiomer, the prefix L is usually omitted (page 3, Chirality, first paragraph).
Regarding instant claims 44 and 59-60, it would have been obvious for a person having ordinary skill in the art to take the pharmaceutical composition administered for the treatment of a solid cancer tumor of ‘059, Harding, Kim, Kang, Rosenthal, and Dix above – and to use the L enantiomer of the histidine buffer because Britannica taught reflecting the near universality of the L enantiomer, the prefix L is usually omitted.
This would produce a liquid pharmaceutical composition for a method of treating a solid cancer tumor (instant claim 60) comprising administering to a human patient an effective amount of a composition of:
10-50 mg/ml of an afucosylated anti-FGFR2IIIb antibody, which overlaps with 20 mg/ml;
20 mM L-histidine, which is a buffer (instant claim 44 and 59);
270 mM sucrose;
0.01% polysorbate 20;
pH 6.0,
wherein the heavy chain comprises Harding SEQ ID NO: 2 and the light chain comprises Harding SEQ ID NO: 3, which is identical to the heavy and light chain of instant SEQ ID NO:2 for VH and SEQ ID NO:3 for VL, wherein the pharmaceutical formulation consists of anti-FGFR2IIIb antibody, histidine buffer, sucrose and polysorbate 20, wherein the formulation does not comprise protein species other than anti-FGFR2 antibody, wherein the composition is contained within in a unit dose single-use vial, wherein the pharmaceutical formulation is not for lyophilization prior to administration to a patient, wherein the antibody lacks fucose at Asn297 because it is afucosylated.
There is a reasonable expectation of success because Britannica taught reflecting the near universality of the L enantiomer, the prefix L is usually omitted. Thus, the L-form of the histidine buffer is what was most likely used in the antibody formulations of ‘100 Harding, Kang, Rosenthal, and Dix.
Response to Arguments
Applicant argues For at least the reasons discussed above regarding the Section 103 rejection, claims 37, 38, 44, 53-56, and 58-60 are not obvious over, and are patentably distinct from, the claims of Harding '059, whether considered alone or in any combination with Harding, King, Kang, Rosenthal, Dix, or Britannica. Accordingly, Applicant respectfully requests withdrawal of the obviousness-type double patenting rejections.
In response, Applicant's arguments filed 3/12/2026 have been fully considered but they are not persuasive. The updated rejection is above. Applicant arguments regarding unexpected results and Harding, Kim, Kang, Rosenthal, Dix, and Britannica are discussed above.
Conclusion
No claims are allowed.
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/J.J.S./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643