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 .
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 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.
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/19/2025 has been entered.
Claims 1, 7-9, and 19-20 were amended. Claims 27-30 were canceled.
Claims 1-2, 4-9, 15-20, and 22-23 are pending in the instant application.
Priority
This application claims priority to the provisional application 62/888086 filed on 8/16/2019.
Claim Interpretation
Claims 19-20 refer to a “histidine-based buffer” this was interpreted as a buffer comprising histidine.
Information Disclosure Statement
The information disclosure statement (IDS) dated 12/19/2025 complies with the provisions of 27 CFR 1.97, 1.98, and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits.
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 1-2, 4-7, 9, 15-19, and 22-23 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.
All except 8, 20
Claim 1 is drawn to the formula comprising “an oligosaccharide” while claim 7 describes several exemplary species of oligosaccharides, most of which are not oligosaccharides or even sugars. The art accepted definitions are (See ChemLibre):
“An oligosaccharide is a carbohydrate whose molecule, upon hydrolysis, yields two to ten Monosaccharide molecules.”
“A monosaccharide is a carbohydrate consisting of one sugar unit.”
“The term carbohydrate comes from the fact that the majority contain carbon, hydrogen, and oxygen in a ratio of 1:2:1,making for an empirical formula of CH2O.”
Specifically, of the examples given, only sucrose and trehalose are art recognized oligosaccharides. Dextrose is an art recognized monosaccharide. Mannitol, Xylitol, and Sorbitol are art recognized sugar alcohols. Whereas TMAO and glycine betaine aren’t chemical related to any sugar. See Table below.
All of the compounds below, excluding TMAO and glycine betaine, are categorized as “polyols”.
Chemical formula
Is a sugar alcohol?
Comprises a monosaccharide?
Is an oligosaccharide?
Sucrose
C12H22O11
n
y
y
Mannitol
C6H14O6
y
n
n
Dextrose
C6H12O6
n
y
n
Glycerol
C3H8O3
n
n
n
TMAO
(CH3)3NO
n
n
n
Trehalose
C12H22O11
n
y
y
Ethylene glycol
C2H6O2
n
n
n
Glycine betaine
C5H11NO2
n
n
n
Xylitol
C5H12O5
y
n
n
Sorbitol
C6H14O6
y
n
n
While Applicant may act as his own lexicographer to specifically define terms of a claim contrary to their ordinary meaning,” in such a situation the written description must clearly redefine a claim term “so as to put a reasonable competitor or one reasonably skilled in the art on notice that the patentee intended to so redefine that claim term.” Applicant provided examples (instant spec pg 2, para 2), but did not provide a definition in the instant specification clearly delineating what “an oligosaccharide” is considered by the applicant. See MPEP § 2173.05(a). As a result one of skill in the art would not be apprised of the metes and bounds of “an oligosaccharide”. Dependent claims 2, 4-7, 9, 15-19, and 22-23 fail to cure these deficiencies, thus are also rendered indefinite. To overcome this rejection, Examiner recommends replacing all instances of “oligosaccharide” with the term “polyol” and removing “TMAO (trimethylamine N-oxide)” and “glycine betaine” from claim 7.
Claim Rejections – 35 USC § 103
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 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 1-9, 12-20, 22, 23, and 27-30 are rejected under 35 U.S.C. 103 as being unpatentable over Ortiz et al. (CA3069756) in view of Kang et al. (https://www.bioprocessintl.com/formulation/rapid-formulation-development-for-monoclonal-antibodies), Wang et al. (doi: 10.1021/acs.molpharmaceut.5b00643), Allan et al. (US20080071063), Shafner et al. (WO2019084438), Devalaraja et al. (Blood 2019; 134 :2278), Devalaraja-Narashimha et al. (US20190177436), Hu et al. (US20170355757) and Szalay et al. (US20160339066). This rejection has been modified to solely address the amendments.
Claim 1, 4
Regarding claims 1 and 4, Ortiz teaches 100 mg/mL or higher of an anti-C5 antibody, this included 200 mg/mL of ravulizumab, also known as BNJ441 and ALXN1210 (pg 2, para 2). Ortiz teaches the pharmaceutically acceptable carrier is water (pg 23, para 2). Ortiz teaches a pharmaceutical formulation comprising water, L-Arginine, and a buffer (pg 68, para 1). Ortiz teaches the formulation can comprise 2% sucrose, (pg 9, para 1), thus satisfying the limitation of comprising an oligosaccharide. Ortiz teaches formulations spanning a pH of 4.23-11.47 (pg 73, Table 5). Ortiz teaches a viscosity of 1.014-10.387 mPa.S, which equals 1.014-10.387 cP (pg 72, Table 4). The instantly claimed quantity of antibody, and pH encompass the ranges of Ortiz, thus rendering obvious the claimed ranges shown in the table below. See MPEP § 2144.05. In the instant case, there is no allegation of criticality or any evidence demonstrating any difference across the range, thus rendering obvious the claimed pH. Furthermore, the formulations of Ortiz comprise overlapping and lower viscosity values than those instantly claimed. Considering that the primary motivation of the instantly claimed invention was to arrive at a high antibody concentration formulation comprising a low viscosity, it appears that the instant invention represents a higher viscosity formulation of Ortiz.
Antibody
pH
viscosity
Instant
180-210 mg/mL
5.5-6.1
8-20 cP
Ortiz
100-200 mg/mL
4.23-11.47
1.014-10.387 cP
Ortiz does not teach the anti-C5 antibody is pozelimab, nor instant SEQ ID NO: 368-369.
Kang teaches the first step in generating an antibody formulation constitutes finding the ideal pH for a given antibody within the range of 4-8 pH units, wherein the antibody is able to be stable for a week at 50°C (pg 42, col 1, para 3). Kang teaches that after the ideal pH is found, an appropriate buffer for that pH range is chosen and excipients such as sugars and salts (pg 42, col 2, para 1-2). Kang teaches the third step involves screening for the ideal concentrations of buffer and excipients under the desired storage temperature and length of time (pg 42, col 3, para 2-3). Kang teaches the process of identifying the ideal formulation for a given antibody takes about 12 weeks (pg 5, para 1). Kang identifies arginine and polysorbate-80 as commonly used excipients in pharmaceutical formulations of antibodies (pg 42, Table 1). Kang identifies sucrose as the most popular excipient in pharmaceutical formulations of antibodies (pg 41, col 3, para 1). Thus Kang’s teachings establish that it is routine optimization to alter these result-effective variables, which were known variables used for a predictable purpose.
Wang teaches “The viscosity of highly concentrated mAb solution is presumably caused by the specific or nonspecific interactions (i.e., H-bonding, hydrophobic, ionic, electrostatic, dipole−dipole, etc.), which is hard to characterize without the molecular details and the three-dimensional structure. [Amino acids] with their diverse side chains have various biophysical−chemical properties.” (pg 4479, col 1, para 2). Wang teaches the amino acid additives, such as arginine and histidine are known to increase enhance stability and reduce viscosity (pg 4479, col 1, para 1). Wang teaches that histidine HCl and arginine HCl significantly decreased the viscosity of formulations of two IgG1 mAbs (pg 4485, col 1, para 2).
Devalaraja teaches the anti-C5 protein, pozelimab, administered as an intravenous solution (pg 1). Pozelimab was compared to other known anti-C5 antibodies, eculizumab and ravulizumab, and exhibited enhanced inhibition of hemolysis over eculizumab and ravulizumab (Figure).
Devalaraja-Narashimha teaches the heavy chain of the anti-C5 antibody, pozelimab, comprising 99.6% sequence identity to instant SEQ ID NO: 368, shown below (SEQ ID NO: 82).
instant_368 QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYN 60
DN_82 QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYN 60
************************************************************
instant_368 PSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQGTLVTVSS 120
DN_82 PSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQGTLVTVSS 120
************************************************************
instant_368 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 180
DN_82 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 180
************************************************************
instant_368 GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV 240
DN_82 GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV 240
************************************************************
instant_368 FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY 300
DN_82 FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY 300
************************************************************
instant_368 RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK 360
DN_82 RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK 360
************************************************************
instant_368 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG 420
DN_82 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG 420
************************************************************
instant_368 NVFSCSVMHEALHNHYTQKSLSLSLGK 447
DN_82 NVFSCSVLHEALHSHYTQKSLSLSLGK 447
*******:*****.*************
Devalaraja-Narashimha teaches the light chain of the anti-C5 antibody, pozelimab, comprising 100% sequence identity to instant SEQ ID NO: 369, shown below (SEQ ID NO: 83)
instant AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPS 60
DN_83 AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPS 60
************************************************************
instant RFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIKRTVAAPSVFIFPP 120
DN_83 RFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIKRTVAAPSVFIFPP 120
************************************************************
instant SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
DN_83 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
************************************************************
instant LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
DN_83 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
**********************************
Hu teaches anti-C5 binding antibodies (para 0002) comprising the heavy chain of SEQ ID NO: 353 (para 0021) and the light chain of SEQ ID NO: 354 (para 0022). Hu teaches 100% sequence identity to instant SEQ ID NO: 368 (SEQ ID NO: 353).
instant_368 QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYN 60
Hu_353 QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYN 60
************************************************************
instant_368 PSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQGTLVTVSS 120
Hu_353 PSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQGTLVTVSS 120
************************************************************
instant_368 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 180
Hu_353 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 180
************************************************************
instant_368 GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV 240
Hu_353 GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV 240
************************************************************
instant_368 FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY 300
Hu_353 FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY 300
************************************************************
instant_368 RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK 360
Hu_353 RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK 360
************************************************************
instant_368 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG 420
Hu_353 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG 420
************************************************************
instant_368 NVFSCSVMHEALHNHYTQKSLSLSLGK 447
Hu_353 NVFSCSVMHEALHNHYTQKSLSLSLGK 447
***************************
Hu teaches 100% sequence identity to instant SEQ ID NO: 369 (SEQ ID NO: 354).
instant_369 AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPS 60
Hu_354 AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPS 60
************************************************************
instant_369 RFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIKRTVAAPSVFIFPP 120
Hu_354 RFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIKRTVAAPSVFIFPP 120
************************************************************
instant_369 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
Hu_354 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
************************************************************
instant_369 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
Hu_354 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
**********************************
llan teaches concentration of antigen-binding protein is 25-200 mg/mL, at least about 250 mg/mL, or at least about 300 mg/mL (pg 7, para 0074), wherein the protein binds the same antigen as eculizumab (pg 37, para 0245), which is a humanized monoclonal antibody targeting C5. Allan teaches the protein can be formulated with a pharmaceutically acceptable carrier (pg 10, para 0080). Allan teaches concentration of antigen-binding protein is 25-200 mg/mL, at least about 250 mg/mL, or at least about 300 mg/mL (pg 7, para 0074). The quantity of protein of Allan encompasses that instantly claimed. In the instant case, there is no allegation of criticality or any evidence demonstrating any difference across the range, thus rendering obvious the instantly claimed protein concentration. See MPEP § 2144.05.
It would have been obvious to combine the teachings of Ortiz, Kang, Wang, Devalaraja, Devalaraja-Narashimha, Hu, and Allan because (1) Ortiz and Allan teach high concentration (~200 mg/mL) formulations of an anti-C5 antibody exist; (2) Kang teaches a 3-stage method of developing a stable pharmaceutical formulation of any antibody; (3) Wang teaches adding arginine as a means of reducing the viscosity of a high concentration antibody formulation; (4) the formulation of Ortiz exhibits the desired viscosity and comprises the same components such as L-arginine and water as instantly claimed; and (5) Devalaraja and Devalaraja-Narashimha provide the amino acid sequence of pozelimab, a known anti-C5 antibody, and (6) Hu provides the sequence identity of the instantly claimed heavy chain variant of pozelimab as being an anti-C5 binding antibody. Thus one of skill in the art need only take the antibody of Devalaraja/Devalaraja-Narashimha (pozelimab) and perform the method of Kang, using the guidance from Ortiz and Allan as starting points in optimizing the formulation of pozelimab in order to arrive at the instantly claimed invention. One of skill in the art would have a had a reasonable expectation of success because Kang teaches the method works to formulate any antibody within 12 weeks and Ortiz teaches it is possible to generate low-viscosity, high-concentration antibody formulations of other anti-C5 antibodies using arginine. Furthermore, given that pozelimab exhibited superior suppression of hemolysis, one would have been motivated to choose pozelimab as the anti-C5 antibody of choice and formulate it with the known low-viscosity formulation of Ortiz.
Claim 2, 6
Regarding claims 2 and 6, Ortiz teaches a pharmaceutical formulation comprising water, L-Arginine, and a buffer (pg 68, para 1). Ortiz teaches the arginine concentration is 15-35 mM (pg 9, para 2). Ortiz teaches formulations spanning a pH of 4.23-11.47 (pg 73, Table 5). Ortiz teaches a viscosity of 1.014-10.387 mPa.S, which equals 1.014-10.387 cP (pg 72, Table 4). The pH range of Ortiz encompasses the pH range instantly claimed. In the instant case, there is no allegation of criticality or any evidence demonstrating any difference across the range, thus rendering obvious the instantly claimed pH. See MPEP § 2144.05. Furthermore, the viscosity of Ortiz overlaps with the viscosity instantly claimed, thus rendering obvious the instantly claimed viscosity. See MPEP § 2144.05. The concentration of arginine of Ortiz is less than that instantly claimed. 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 the instant case, applicant has not provided any evidence of criticality, thus arriving at an optimal arginine concentration of 100 mM of arginine, thus arriving at this particular concentration is considered a matter of routine experimentation. See MPEP § 2144.05(II)(A).
Claim 5
Regarding claim 5, Ortiz teaches including the excipient L-Arginine HCl (pg 73, Table 5).
Additionally, Wang teaches that arginine HCl can significantly decrease the viscosity of an antibody formulation (pg 4485, col 1, para 2).
Claim 7-9
Regarding claims 7-9, Ortiz teaches the oligosaccharide, sucrose, in a concentration of 2-10% (w/v) (pg 5, para 2). This range encompasses the range of sucrose concentration instantly claimed. In the instant case, there is no allegation of criticality or any evidence demonstrating any difference across the range of sucrose concentration, thus rendering obvious the claimed range. See MPEP § 2144.05.
Kang teaches that sucrose is a common excipient used in antibody formulations (pg 42, Table 1).
Allan teaches the formulation comprising the oligosaccharide, sucrose (pg 2, para 0014), at a concentration of 1-15% (w/v) (pg 2, para 0013). The quantity of sucrose of Allan encompasses that instantly claimed. In the instant case, there is no allegation of criticality or any evidence demonstrating any difference across the range, thus rendering obvious the sucrose concentration. See MPEP § 2144.05.
Claim 15
Regarding claim 15, Ortiz teaches the buffer concentration is about 20 mM (pg 6 para 2). This range encompasses the exact range instantly claimed, thus rendering obvious the claimed buffer concentration. See MPEP § 2144.05. Ortiz teaches histidine as the buffer (pg 5, para 3).
Additionally, Allan teaches the buffering agent is histidine (pg 2, para 0014), at a concentration of 1-50 mM (pg 1, para 002). The concentration of Allan encompasses that instantly claimed. In the instant case, there is no allegation of criticality or any evidence demonstrating any difference across the range, thus rendering obvious the histidine concentration. See MPEP § 2144.05.
Claim 16-17
Regarding claim 16 and 17, Ortiz teaches the non-ionic detergent is polysorbate-80 (pg 7, para 2).
Kang teaches that polysorbate-80 is a commonly used excipient in antibody formulations (pg 42, Table 1).
Additionally, Allan teaches the non-ionic detergent, polysorbate 80 (pg 9, para 0078), at a concentration between 0.001-1.00%, or about 0.1% (w/v) (pg 10, para 0078). The concentration of Allan encompasses that instantly claimed. In the instant case, there is no allegation of criticality or any evidence demonstrating any difference across the range, thus rendering obvious the instantly claimed polysorbate-80 concentration. See MPEP § 2144.05. Allan teaches the formulations of the present invention can be administered by injection (pg 36, para 0220
Claim 18
Regarding claim 18, Ortiz teaches the concentration of non-ionic detergent is about 0.15% (pg 8, para 1). This range encompasses the exact range instantly claimed, thus rendering obvious the claimed detergent concentration. See MPEP § 2144.05.
Claim 19-20
Regarding claims 19 and 20, Allan teaches concentration of antigen-binding protein is 25-200 mg/mL, at least about 250 mg/mL, or at least about 300 mg/mL (pg 7, para 0074), a buffer of 1-100 mM (claim 1) such as histidine (claim 6), 35-200 mM of arginine (claim 36, 38), 1-20% (w/v) carbohydrate (claim 1), such as sucrose (claim 7), 0.001-0.1% (w/v) detergent such as polysorbate-80 (claim 20 and 19), at a pH of 5.5-8.0 (claim 1), and water (pg 36 para 0220). The concentrations of Allan encompasses that instantly claimed. In the instant case, there is no allegation of criticality or any evidence demonstrating any difference across the range, thus rendering obvious the instantly claimed protein, histidine, arginine, sucrose, and polysorbate-80 concentrations, in addition to the pH. See MPEP § 2144.05.
Allan does not teach that the anti-C5 antibody is pozelimab.
Kang teaches that arginine, histidine, sucrose, and polysorbate-80 are commonly used excipients in antibody formulations (pg 42, Table 1).
Wang teaches that high concentration antibody formulations, if their viscosity is too high, are difficult to for injecting subcutaneously, thus one must optimize such formulations to lower their viscosity by including viscosity-lowering excipients such as arginine or histidine (abstract).
Devalaraja teaches the anti-C5 protein, pozelimab, administered as an intravenous solution (pg 1). Pozelimab was compared to other known anti-C5 antibodies, eculizumab and ravulizumab (Figure).
It would have been obvious to combine the teachings of Ortiz, Kang, Wang, Allan, and Devalaraja because (1) the formulations of Ortiz and Allan teach high concentration formulations of anti-C5 antibodies can be achieved at a low viscosity; (2) Kang teaches histidine, arginine, and polysorbate-80 are commonly used excipients in antibody formulations; (3) Wang teaches that histidine and arginine can lower the viscosity of high concentration antibody formulations; (4) the formulations of Ortiz and Allen comprise the same components in similar concentrations as instantly claimed: polysorbate-80, histidine buffer, oligosaccharide, sucrose, L-arginine, and water; (5) Devalaraja teaches pozelimab is an effective anti-C5 antibody, and (6) all of the references excluding Kang describe administering the antibody via injection. Thus one of skill in the art would have been motivated to select pozelimab, given the guidance of Devalaraja and use the teachings of Kang, Wang, Ortiz, and Allan in order to arrive at a formulation suitable for injection comprising the instantly claimed components at the instantly claimed quantities.
Claim 22-23
Regarding claims 22 and 23, Ortiz teaches the formulation in association with a further therapeutic agent, such as a corticosteroid (pg 61, para 3).
Additionally, Allan teaches the protein may be utilized in combination with another therapeutic agent (pg 33, para 0203). Allan teaches the agent may be conjugated to the protein, such as a glucocorticoid, thus meeting the limitation of “corticosteroid” (pg 25, para 0156).
Response to Arguments
Applicant's arguments filed 12/19/2025 have been fully considered but they are not persuasive.
103; pg 6, para 3-pg 8, para 1
Applicant argues “none of the cited references discloses a formulation containing the claimed anti-C5 antibody (e.g. pozelimab) at the claimed high concentration of about 180-210 mg/ml, and the choice of antibody in the formulation is significant.” Applicant argues that antibody formulations must be made individually and that their stability cannot be predicted a priori.
While it is appreciated that antibody formulations must be made on an individual basis, Applicant’s analysis excludes the reference of Kang, who teaches a stepwise method for optimizing a formulation for any given antibody (regardless of its sequence) and also fails to include the reference of Devalaraja-Narashimha who teaches pozelimab may be formulated with known excipients for subcutaneous administration. Kang teaches the first step in generating an antibody formulation constitutes finding the ideal pH for a given antibody within the range of 4-8 pH units, wherein the antibody is able to be stable for a week at 50°C (pg 42, col 1, para 3). Kang teaches that after the ideal pH is found, an appropriate buffer for that pH range is chosen and excipients such as sugars and salts (pg 42, col 2, para 1-2). Kang teaches the third step involves screening for the ideal concentrations of buffer and excipients under the desired storage temperature and length of time (pg 42, col 3, para 2-3). Kang teaches the process of identifying the ideal formulation for a given antibody takes about 12 weeks (pg 5, para 1). Kang identifies sucrose as the most popular excipient in pharmaceutical formulations of antibodies (pg 41, col 3, para 1). Thus Kang’s teachings establish that it is routine optimization to alter these result-effective variables, which were known variables used for a predictable purpose. Secondly, Devalaraja-Narashimha teaches pozelimab may be admixed with a pharmaceutically acceptable carrier or excipient as detailed in Remington’s Pharmaceutical Sciences (para 0082) in order to generate a formulation that is amenable to subcutaneous administration (para 0086). The reference of Ortiz supplies an exemplary anti-C5 antibody formulation as guidance when performing the method of Kang. In addition, the reference of Allan supplies an exemplary formulation for any antibody comprising a modified Fc region. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
103; pg 8, para 2-pg 9, para 3
Applicant argues “the claimed formulations satisfy a long felt need by providing a high concentration formulation that can be conveniently administered by a patient at home”. Applicant argues the instant invention provides greater convenience: “the presently claimed high concentration formulations are suitable for administration subcutaneously at low volume by a patient at home (e.g., by autoinjector).”
Applicant has not provided evidence for the absence of these formulations or established such assertions in a declaration. Furthermore, these assertions don’t address any particular deficiency in the rejections made. Because the excipients histidine and arginine are known viscosity reducers (as taught by Wang in the 103 rejection above), the absence of any particular concentration of histidine or arginine in instant claims 1, 4-5, 7-9, 15-18, and 22-23 undermines the assertions towards achieving a surprisingly low viscosity. Thus Applicant’s arguments are not commensurate in scope with the instant claims. Applicant has also failed to present any evidence of criticality over any of the instantly claimed ranges of excipients, thus the instantly claimed formula appears to be one of many that could be obtained using routine optimization under the guidance of Kang.
103; pg 9, para 4-pg 10, para 1
Applicant argues “it would not have been obvious to include an oligosaccharide in a high concentration antibody formulation designed to have low viscosity because oligosaccharides are conventionally thought to increase viscosity.”
Firstly, it is appreciated that oligosaccharides (using the art-recognized term) increase the viscosity of an antibody formulation (see He et al., doi: 10.1007/s11095-011-0388-7). In order to arrive at a conclusion of surprising results, Applicant must first identify a trend then describe how the instant invention deviates from that trend. In the instant case, Table 8-1 (reproduced below) shows the viscosity of pozelimab formulations comprising 20 mM histidine, pH 5.8, 100 mM L-arginine hydrochloride, 2% (w/v) sucrose, 0.15% (w/v) polysorbate 80; wherein the concentration of pozelimab and the temperature is varied.
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498
909
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If applicant could supply the evidence showing that a formulation lacking sucrose exhibited enhanced viscosity, that would provide sufficient support to rebut a conclusion of obviousness. Alternatively, evidence showing that formulations comprising less sucrose exhibited greater viscosity would also rebut a conclusion of obviousness. Lacking that, any evidence showing criticality across one of the concentrations of claimed excipients may provide support in favor of rebutting a conclusion of obviousness (e.g. loss of formulation stability if too much or too little sucrose was included in the formula).
Secondly, because only claims 8 and 20 require the inclusion of an art-recognized oligosaccharide (sucrose), applicant should be made aware that the conclusion of obviousness can only be rebutted if the surprising results are commensurate in scope with the claims. See 112(b) rejection above.
Conclusion
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/L.A.E./
Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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