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 .
2. Applicant’s amendment filed on 04/09/2026 is acknowledged.
3. Claims 1-9 and 11-15 are pending and under consideration for their full scope.
4. Applicant’s IDS documents filed on 04/09/2026 has been considered.
5. The following rejections are necessitated by the amendment filed on 04/09/2026.
6. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
7. Claims 3 and 13 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 3 has been amended to recite “The pharmaceutical composition according to comprising the combination of 50 mM of arginine and 250 mM of histidine, the combination of 150 mM of arginine and 150 mM of histidine, or the combination of 250 mM of arginine and 50 mM of histidine” but this is not further limiting to the recitations of claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
8. 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.
9. Claims 1-9, 11 and 13-15 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “the combination of arginine and histidine at a total concentration of 200 to 400 mM” and this recitation is unclear and indefinite. It is improper to say arginine and histidine at a total concentration of 200 to 400 mM. One cannot cite the concentration of two molecules as 200 to 400 mM. One calculates molar concentration of a particular solute by the amount of the particular solute (in moles) dissolved in a specific volume of solution. One cannot add molar concentrations together to arrive at a “combined” molar concentration of a solution when both solutes are present in the same solution.
There is no definition in the specification of the term “total concentration” and it is completely unclear what is meant by this recitation.
Correction is required.
10. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
11. Claims 1-9, 11 and 13-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a New Matter rejection for the following reasons:
Applicant’s amendment on 04/09/2026 asserts that no New Matter has been added and points to “the original claims and throughout the specification” for support for the newly added limitations. However, the specification does not appear to provide an adequate written description of a pharmaceutical composition comprising an anti-fractalkine antibody, wherein said pharmaceutical composition comprises 200 mg/mL of said anti-fractalkine antibody and “the combination of arginine and histidine at a total concentration of 200 to 400 mM” of claim 1. The instant claims now recite limitations which were not clearly disclosed in the specification and claims as filed, and now change the scope of the instant disclosure as filed. Such limitations recited in the present claims, which did not appear in the specification or original claims, as filed, introduce new concepts and violate the description requirement of the first paragraph of 35 U.S.C. 112.
Applicant is required to cancel the New Matter in the response to this Office Action.
Alternatively, Applicant is invited to clearly point out the written support for the instant limitations.
12. 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.
13. 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.
14. Claims 1-9 and 11-15 are rejected under 35 U.S.C. 103 as being unpatentable over EP 3159007 (IDS filed on 08/22/2024; Reference 1) in view of Ohtake et al. (PTO-892 mailed on 10/15/2026; Reference U) and Zadar et al. (PTO-892 mailed on 10/15/2026; Reference V).
EP 3159007 teaches an anti-fractalkine antibody of SEQ ID NOs 13 and 14; and SEQ ID Nos 11 and 12 wherein the antibody is IgG2 isotype and comprising amino acid substitutions V234A and G237A in the Fc region. (In particular, page 2, lines 44-58). The reference teaches the antibody formulation for subcutaneous administration (page 8, line 34); (further comprising histidine (page 8, line 23); polysorbate 80 at concentration of .01-1.0 (page 8, lines 17-18); further comprising histidine, citrate (citric acid salt), , glycine and acetate buffer and p25 mM phosphate buffered saline which comprises sodium phosphate (Table 2); and wherein 200 mg of the H3-2L4 anti-fractaline antibody comprising SEQ ID NOs 11 and 12; 13 and 14 is subcutaneously administered (In particular, Example 2)
Instant/reference SEQ ID NO:13 are 100% sequence identical over length and sequence. Instant/reference SEQ ID NO:14 are 100% sequence identical over length and sequence. Instant/ reference SEQ ID NO:11 are 100% sequence identical over length and sequence. Instant/ reference SEQ ID NO:12 are 100% sequence identical over length and sequence.
The claimed invention differs from the prior art in the recitation of a pharmaceutical composition comprising the antibody at a concentration of 200 mg/mL and 200 to 400 mM of arginine, 200 to 400 mM of histidine, or the combination of arginine and histidine at a total concentration of 200 to 400 mM of claim 1; further comprising lysine and/or ornithine of claim 2; comprising the combination of 50 mM of arginine and 250 mM of histidine, the combination of 150 mM of arginine and 150 mM of histidine, or the combination of 250 mM of arginine and 50 mM of histidine of claim 3; comprising 200 to 400 mM of arginine of claim 4; wherein the arginine is 250mM of claims 5 and 12.
Ohtake et al. teaches that high concentration antibody formulations often become too viscous to inject. It takes several minutes to inject a small volume of the formulation, as shown in Fig. 18. Addition of arginine at ≥0.15 M reduced the viscosity, and its inclusion may allow for shorter administration time. Such effect of arginine on high protein concentration formulation may be a viable approach for reducing the formulation viscosity (In particular, page 1065-1068, whole document).
Zidar et al. teaches viscosity presents a major challenge in the formulation development of therapeutic proteins, such as monoclonal antibodies, where highly concentrated protein formulations (protein concentration of over 100 mg/ml) for subcutaneous administration are in great demand as an alternative route to low concentration formulations that are delivered intravenously. Highly concentrated formulations are inherently overly viscous and therefore difficult to inject due to the large force needed to expel them through a needle. Viscosity value of 15 cP is targeted in biopharmacy. Controllably lowering the viscosity of an aqueous protein solution has inherent challenges in a biopharmaceutical setting, where viscosity control is directly linked with potency of the dose. (In particular, pages 309, 313 and 315, whole document).
Zidar et al teaches that the upper protein concentration limit in all liquid biologics of around 200 mg/ml based on the separate quantification of contributions to viscosity. A high portion of steric and hydrodynamic interactions to viscosity as determined from intrinsic viscosity measurements limits the effectiveness of viscosity-reducing additives – even if all residual forces in our system were screened, the maximum achievable concentration would not have significantly exceeded 200 mg/ml. (In particular, page 315, last paragraph, whole document).
Zidar et al teaches that arginine was the most effective viscosity reducing agent among lysine, histidine and arginine and that arginine reduced viscosity by 50%. The reference teaches an equation for determining the reduction in viscosity for given protein and viscosity reducing agent concentration. (In particular, page 313, whole document)
It would have been obvious to one of ordinary skill in the art at the time of invention to have prepared the antibody of EP 3159007 in as concentrated a form as possible for subcutaneous administration given that the dose of antibody required to perform the biological function in vivo was high at 200 mg. As such, it would have been obvious to one of ordinary skill in the art to have prepared a highly concentrate solution for subcutaneous administration . Since highly concentrated formulations are inherently overly viscous and therefore difficult to inject due to the large force needed to expel them through a needle, and because it takes several minutes to inject a small volume of a concentrated antibody formulation, one of ordinary skill in the art would have sought to reduce the viscosity of the solution. As such, it would have been obvious to one of ordinary skill in the art at the time of invention to have looked to the art of Zidar for ways to reduce viscosity of antibody formulations using arginine, lysine and histidine. Since Zidar et al. teaches that arginine had the best viscosity reducing properties it would have been obvious to have preferentially used arginine. It would have been obvious to have used 120 mM arginine, lysine or histidine buffers since that is the concentration used in the viscosity study for antibodies at concentration 150 mg/ml. For higher antibody concentrations it would have been obvious to have increased the arginine, lysine or histidine proportionally with the concentration of the antibody by using the equation presented in the Zidar reference as a guide for selecting the concentrations to obtain optimal viscosity of 15 cP.
It would also have been obvious to one of ordinary skill in the art at the time Applicant's invention was made to determine all operable features of optimal concentrations of the components because as evidence by the art of Zadar, concentration of antibodies and viscosity reducing agents are art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art of manufacturing highly concentrated antibody solutions. The determination of the optimal concentrations of the components is well within the purview of one of ordinary skill in the art at the time the invention was made and lend no patentable import to the claimed invention. It has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP § 2144.05 part II.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant’s arguments filed on 04/09/2026 have been fully considered, but are not found persuasive.
Applicant argues:
Applicant respectfully traverses the rejection of the remaining claims in view of the claim amendments and the following remarks.
As described in the working examples of the present application, a formulation containing the anti-fractalkine antibody H3-2L4 at a concentration of 200 mg/ml was found to have a high viscosity, exceeding 50 centipoise (cP). See specification at Example 2, Table 1. High viscosity in antibody formulations is associated with problems such as syringe clogging, increased slide resistance (the force required for administration), diminished accuracy of quantification for administration/manufacture, and reduction in packing speed for manufacture. See specification at page 2, paragraph [0006]. The inventors investigated whether a formulation could be prepared that contains the H3-2L4 antibody at a concentration of 200 mg/ml while having a low viscosity. Several additives were assessed for their ability to reduce viscosity of a formulation containing the antibody at 200 mg/ml. Of the various additives and concentrations evaluated, the inventors determined that viscosity could be reduced below 15 cP if the formulation contained 200 to 400 mM of arginine, 200 to 400 mM of histidine, or the combination of arginine and histidine at a total concentration of 200 to 400 mM. See specification at Example 2, Tables 1 and 2.
Consistent with the inventors' experimental findings, amended independent claim 1 is directed to a pharmaceutical composition comprising 200 mg/ml of an anti-fractalkine antibody and 200 to 400 mM of arginine, 200 to 400 mM of histidine, or the combination of arginine and histidine at a total concentration of 200 to 400 mM, wherein the anti-fractalkine antibody comprises the amino acid sequences of the heavy chain variable region and light chain variable region of the H3-2L4 antibody and a constant region of human IgG2 isotype comprising amino acid substitutions V234A and G237A in the Fc region. Independent claim 12 is directed to a pharmaceutical composition comprising, among other things, 200 mg/ml of the anti-fractalkine antibody and 250 mM of arginine.
To establish a primafacie case of obviousness, there must be, inter alia, a rationale based in the prior art to modify or combine the prior art and a reasonable expectation of success. MPEP § 2143. "An obviousness determination requires finding that a person of ordinary skill in the art would have been motivated to combine or modify the teachings in the prior art and would have had a reasonable expectation of success in doing so." Regents of Univ. of Cal. v. Broad Inst., Inc., 903 F.3d 1286, 1291 (Fed. Cir. 2018) (emphasis added).
Applicant respectfully submits that nothing in Yasuda, Ohtake, and Zidar would have provided the person of ordinary skill in the art with a reason or rationale to prepare a pharmaceutical formulation containing the H3-2L4 antibody at a concentration of 200 mg/ml, much less a basis to expect that a formulation containing the H3-2L4 antibody at a concentration of 200 mg/ml could be made to have a low level of viscosity by inclusion of 200 to 400 mM of arginine, 200 to 400 mM of histidine, or the combination of arginine and histidine at a total concentration of 200 to 400 mM. In the absence of a rationale to modify or combine the prior art to arrive at the claimed invention and a reasonable expectation of success in doing so, the person of ordinary skill in the art would have had no reason to prepare the claimed pharmaceutical composition.
Yasuda describes, among other things, clinical trials in which the H3-2L4 antibody was administered to healthy subjects and subjects with rheumatoid arthritis. See Yasuda Examples 2 and 3, respectively. In these clinical trials, doses of 50 mg, 100 mg, 200 mg, or 400 mg of H3- 2L4 were delivered by subcutaneous administration of an aqueous solution containing H3-2L4 at a concentration of 100 mg/mL, 25 mM phosphate buffer (pH 5.8), 200 mM sucrose, 50 mM glycine, and 0.05% polysorbate 80. Id. Notably, Yasuda's subcutaneous formulation contains H3-2L4 at 100 mg/mL, which is half of the 200 mg/mL antibody concentration used in the claimed pharmaceutical composition. Furthermore, the formulation used in Yasuda's clinical trials contains no arginine or histidine at all, much less the 200 to 400 mM of arginine and/or histidine required by the present claims.
As described in Wang et al. (2021) Antibody Therapeutics 4(4):262-73 (a copy of which is included in an Information Disclosure Statement submitted herewith), a 100 mg/ml antibody formulation is considered a "high concentration" antibody formulation and is an antibody concentration present in many "high concentration" formulations approved by the FDA for subcutaneous administration. Given that Yasuda already described a high concentration antibody formulation (100 mg/ml) that was used for subcutaneous administration of all antibody doses tested to subjects with rheumatoid arthritis, the skilled person having read Yasuda would have had no reason or rationale to set aside the H3-2L4 formulation used by Yasuda and prepare a different antibody formulation, containing H3-2L4 at the greatly increased concentration of 200 mg/ml. Furthermore, nothing in Yasuda would have caused the skilled person to expect that inclusion of arginine, histidine, or the combination thereof at a concentration of 200 to 400 mM in a formulation containing H3-2L4 at 200 mg/ml would result in a formulation having an acceptably low level of viscosity.
Ohtake and Zidar do not add what is lacking in Yasuda. Ohtake is a review article describing formulation excipients used to stabilize proteins, suppress protein aggregation, reduce surface adsorption, or provide physiological osmolality. The Office Action cited a passage of Ohtake describing use of arginine as an excipient, which passage states that "[h]igh concentration antibody formulations often become too viscous to inject" and "[a]ddition of arginine at >0.15M reduced the viscosity, and its inclusion may allow for shorter administration time." Ohtake at page 1065, right column. This general passage about the potential benefits of including arginine in a "high concentration" antibody formulation would have provided the person of ordinary skill in the art with no basis to reasonably expect that it would be possible to prepare a formulation containing the H3-2L4 antibody at a concentration of 200 mg/ml and a viscosity below 15 cP, much less that such a high antibody concentration/low viscosity formulation could be made by inclusion of 200 to 400 mM of arginine, 200 to 400 mM of histidine, or the combination of arginine and histidine at a total concentration of 200 to 400 mM.
Zidar describes mechanisms of controlling the viscosity of concentrated protein solutions by using viscosity-reducing additives ("VRAs"), such as arginine or histidine. However, Zidar concluded that the effectiveness of VRAs at reducing viscosity is diminished as protein concentration increases to high levels, stating that [i]n the presented system, even though the viscosity could be reduced by half at any given concentration by VRAs, the protein concentration could only be increased by around 20% to reach the viscosity limit again due to the exponential increase of viscosity with concentration - from 150 mg/ml to 175 mg/ml. A high proportion of steric and hydrodynamic interactions to viscosity as determined from intrinsic viscosity measurements limits the effectiveness of viscosity- reducing additives - even if all residual forces in our system were screened, the maximum achievable concentration would not have significantly exceeded 200 mg/ml. Since the magnitude of steric/hydrodynamic interactions depends primarily on the volume fraction of the protein, this limitation is general for all
liquid protein formulations, with slight variations due to protein shape which defines the intrinsic viscosity. This is reflected on the market as well, with the protein concentration of liquid biologics rarely exceeding 175 mg/ml. If such a concentration is not sufficient in a given biopharmaceutical system, this approach could be combined with hyaluronidase enzyme or an aqueous solution of proteins could changed to a non-aqueous suspension, potentially reaching up to 300 mg/ml or more. Zidar at page 315, right column, to page 316 left column (emphasis added).
The above passage of Zidar establishes that an exponential increase in viscosity occurs when increasing protein concentration from 150 mg/ml to 175 mg/ml, making it unpredictable whether a formulation can be prepared for any given antibody at a concentration of 200 mg/ml. Zidar states that the viscosity-driven limitations associated with formulation preparation are the reason why marketed biologics rarely have a protein concentration exceeding 175 mg/ml.
The Wang et al. publication submitted herewith is a review of FDA-approved antibody formulations containing antibodies at a "high concentration" (defined by Wang et al. as at least 100 mg/ml). Of the 34 FDA-approved high concentration antibody formulations described by Wang et al., 30/34 have an antibody concentration in the range of 100-150 mg/ml, one has an antibody concentration of 175 mg/ml, one has an antibody concentration of 180 mg/ml, and two have an antibody concentration of 200 mg/ml. The relatively few number of "high concentration" formulations having an antibody concentration of 200 mg/ml (2/34) is consistent with Zidar's statement that the protein concentration of liquid biologics rarely exceeds 175 mg/ml due to viscosity-driven limitations.
Of the two formulations described by Wang et al. that contain an antibody concentration of 200 mg/ml, one contains arginine at a concentration of 25 mM (5.3 mg/ml) and the other does not contain arginine at all. Notably, neither of the two 200 mg/ml antibody formulations described by Wang et al. contains arginine at or near the concentration of 200 to 400 mM required by the claims. Of the 32 other "high concentration" formulations described by Wang et al. (which have antibody concentrations of at least 100 mg/ml but less than 200 mg/ml), only eight contain arginine and of those only a single formulation contains an arginine concentration of at least 200 mM (see page 266 Wang et al., describing Xolair as containing the antibody at a concentration of 125 mg/ml and arginine at 42.1 mg/ml, which is the equivalent of 200 mM).
Ohtake and Zidar, as well as the enclosed publication of Wang et al., collectively establish that the field of high concentration antibody formulations is unpredictable, such that it cannot be predicted whether a given antibody can be formulated at a concentration of 200 mg/ml, much less what additives and associated concentrations could be used to make a formulation containing the antibody at a concentration 200 mg/ml while having an acceptable level of viscosity. It was in the face of this unpredictability that the skilled person at the time the present application was filed would have had no basis to prepare the claimed pharmaceutical composition with a reasonable expectation of success.
In view of the claim amendments and the foregoing remarks, Applicant respectfully submits that there is no experimental data or other teaching in Yasuda in combination with Ohtake and Zidar that would have provided the skilled person with a reason or rationale to seek to prepare an antibody formulation containing the H3-2L4 antibody at a concentration of 200 mg/ml, much less a basis to reasonably expect that inclusion of 200 to 400 mM of arginine, 200 to 400 mM of histidine, or the combination of arginine and histidine at a total concentration of 200 to 400 mM in a formulation containing the H3-2L4 antibody at a concentration of 200 mg/ml would result in an acceptably low level of viscosity. As a result, the references do not render obvious the pharmaceutical composition of independent claims 1 or 12 or the claims that depend directly or indirectly therefrom.”
It is the Examiner’s position that Applicant’s arguments directed to the motivation to make a 200 mg/mL solution is unpersuasive. There is always motivation to make as concentrated a solution as possible for an injectable formulations. In addition, the art of EP 3159007 actually teaches the use of a 200 mg. As such, no additional motivation is needed to make a 200 mg/mL solution.
So, then one only has to look for the motivation for adding the addition components recited in the claims. It is the Examiner’s position that there is no criticality in the recited concentrations of arginine and histidine as evidenced by the disclosure throughout the entire specification. Furthermore, there is no viscosity recited in the claims so Applicant is arguing limitations that are not present in the claims.
It also appears that Applicant may be intending for the recitation of “the combination of arginine and histidine at a total concentration of 200 to 400 mM” to encompass and two separate molar concentrations that add up to 200 mM or 400mM. This recitation is not problematic for the reasons cited supra. Additionally this shows that any amount of optimization within the recited range is acceptable and will work which is what is expected in view of the art. Arginine and histidine were well known in the art at the time of invention to reduce viscosity of antibody formulations and it would have been obvious to have optimized the concentration of one or both to have arrived at a formulation with the lowest viscosity for injection.
The rejection stands for reasons of record.
15. Claims 1-9 and 11-15 are rejected under 35 U.S.C. 103 as being unpatentable over EP 3159007 (IDS filed on 08/22/2024; Reference 1) in view of U.S. Patent Application Publication 2012/0064086 (PTO-892; Reference A).
EP 3159007 teaches an anti-fractalkine antibody of SEQ ID NOs 13 and 14; and SEQ ID Nos 11 and 12 wherein the antibody is IgG2 isotype and comprising amino acid substitutions V234A and G237A in the Fc region. (In particular, page 2, lines 44-58). The reference teaches the antibody formulation for subcutaneous administration (page 8, line 34); (further comprising histidine (page 8, line 23); polysorbate 80 at concentration of .01-1.0 (page 8, lines 17-18); further comprising histidine, citrate (citric acid salt), , glycine and acetate buffer and p25 mM phosphate buffered saline which comprises sodium phosphate (Table 2); and wherein 200 mg of the H3-2L4 anti-fractaline antibody comprising SEQ ID NOs 11 and 12; 13 and 14 is subcutaneously administered (In particular, Example 2)
Instant/reference SEQ ID NO:13 are 100% sequence identical over length and sequence. Instant/reference SEQ ID NO:14 are 100% sequence identical over length and sequence. Instant/ reference SEQ ID NO:11 are 100% sequence identical over length and sequence. Instant/ reference SEQ ID NO:12 are 100% sequence identical over length and sequence.
The claimed invention differs from the prior art in the recitation of a pharmaceutical composition comprising the antibody at a concentration of 200 mg/mL and 200 to 400 mM of arginine, 200 to 400 mM of histidine, or the combination of arginine and histidine at a total concentration of 200 to 400 mM of claim 1; further comprising lysine and/or ornithine of claim 2; comprising the combination of 50 mM of arginine and 250 mM of histidine, the combination of 150 mM of arginine and 150 mM of histidine, or the combination of 250 mM of arginine and 50 mM of histidine of claim 3; comprising 200 to 400 mM of arginine of claim 4; wherein the arginine is 250mM of claims 5 and 12.
U.S. Patent Application Publication 2012/0064086 teaches in paragraphs [0005]-[0014]
“There is a significant demand for highly concentrated liquid antibody formulations. However, highly concentrated protein formulations pose several problems.
One problem is instability due to the formation of particulates. With reconstituted lyophilized preparations to generate liquid formulations, this problem has been addressed through the use of surfactants (e.g., a polysorbate), but surfactants are unsuitable for liquid formulations, because they render further processing difficult. Moreover, surfactants further do not reduce the increased viscosity caused as a result of numerous intermolecular interactions from the macromolecular nature of antibodies.
Although surfactants have been shown to significantly reduce the degree of particulate formation of proteins, they do not address the problem of increased viscosity that makes difficult the manipulation and administration of concentrated antibody formulations. Antibodies tend to form viscous solutions at high concentration because of their macromolecular nature and potential for intermolecular interactions. Moreover, pharmaceutically acceptable sugars are often used in large amounts as stabilizers. Such sugars can enhance the intermolecular interactions, thereby increasing the viscosity of the formulation. Highly viscous formulations are difficult to manufacture, draw into a syringe and inject subcutaneously. The use of force in manipulating the viscous -formulations leads to excessive frothing, which can lead to denaturation and inactivation of active biologics. Satisfactory solution of this problem is lacking.
While the prior art indicates numerous example of excipients that can be suitably employed to create pharmaceutical formulations, very few proteins have been successfully formulated above 100 mg/ml, or have techniques for doing so been described.
Applicants have discovered that Arginine, specifically Arginine-HCI is particularly suited for highly concentrated liquid protein or antibody formulations.”
“The present invention concerns highly concentrated protein or antibody formulations that are stable, and of low viscosity and turbidity.
In particular, the present invention concerns highly concentrated antibody formulations of low turbidity comprising protein or antibody (100 - 260 mg/ml), histidine (10 - 100 mM), arginine-HCI (50 - 200 mM) and polysorbate (0.01% - 0.1%), having a pH of 5.5 - 7.0, a viscosity of 50 cs or less and osmolarity from 200 mOsm/kg - 450 mOsm/kg.
Alternatively, the protein or antibody in the formulations can range from 120 - 260 mg/ml, alternatively 150 - 260 mg/ml, alternatively 180 -260 mg/ml, alternatively 200 - 260 mg/ml protein or antibody. Alternatively the osmolarity ranges from 250 mOsm/kg - 350 mOsm/kg. Alternatively, the concentration of arginine-HCl ranges from 100 - 200 mM, alternatively 150 - 200 mM, alternatively 180 - 200 mM.
In a particular embodiment, the invention provides a formulation containing high concentrations of large molecular weight proteins, such as antibodies or immunoglobulins. The antibodies may, for example, be antibodies directed against a particular predetermined antigen.”
The reference teaches the addition of lysine, phosphoric acid, citric acid, succinic acid, and sodium phosphate.
The reference claims:
1.A stable, liquid formulation of low turbidity comprising (a) a protein or antibody in an amount of 100 to 260 mg/ml, (b) arginine-HCI in an amount of 50 to 200 mM, (c) histidine in an amount of 10 to 100 mM, (d) polysorbate in an amount of 0.01 to 0.1%, where the formulation further has a pH ranging from 5.5 to 7.0, a kinematic viscosity of about 50 cs or less and osmolarity ranging from 200 mOsm/kg to 450 mOsm/kg.
2. The formulation of Claim 1, wherein the concentration of protein or antibody ranges from 120 mg/ml to 260 mg/ml.
3. The formulation of Claim 1, wherein the concentration of protein or antibody ranges from 150 mg/ml to 260 mg/ml.
4. The formulation of Claim 1, wherein the concentration of protein or antibody ranges from 180 mg/ml to 260 mg/ml.
5. The formulation of Claim 1, wherein the concentration of protein or antibody ranges from 200 mg/ml to 260 mg/ml.
8. The formulation of Claim 1, wherein the concentration of arginine-HCI ranges from 100 mg/ml to 200 mg/ml.
It would have been obvious to one of ordinary skill in the art at the time of invention to have prepared the antibody of EP 3159007 in as concentrated a form as possible for subcutaneous administration given that the dose of antibody required to perform the biological function in vivo was subcutaneously injected as high at 200 mg. As such, it would have been obvious to one of ordinary skill in the art to have prepared a highly concentrate solution for subcutaneous administration . Since highly concentrated formulations are inherently overly viscous and therefore difficult to inject due to the large force needed to expel them through a needle, and because it takes several minutes to inject a small volume of a concentrated antibody formulation, one of ordinary skill in the art would have sought to reduce the viscosity of the solution. As such, it would have been obvious to one of ordinary skill in the art at the time of invention to have looked to the art of U.S. Patent Application Publication 2012/0064086 for ways to reduce viscosity of antibody formulations using arginine. Since U.S. Patent Application Publication 2012/0064086 teaches that arginine Arginine-HCI is particularly suited for highly concentrated liquid protein or antibody formulations it would have been obvious to have preferentially used arginine. It would have been obvious to have used arginine and histidine and lysine buffers since the art of U.S. Patent Application Publication 2012/0064086 teaches their combined use for antibody formulations. For higher antibody concentrations it would have been obvious to have increased the arginine, lysine or histidine proportionally with the concentration of the antibody.
It would also have been obvious to one of ordinary skill in the art at the time Applicant's invention was made to determine all operable features of optimal concentrations of the components because as evidence by the art of U.S. Patent Application Publication 2012/0064086, concentration of antibodies and viscosity reducing agents are art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art of manufacturing highly concentrated antibody solutions. The determination of the optimal concentrations of the components is well within the purview of one of ordinary skill in the art at the time the invention was made and lend no patentable import to the claimed invention. It has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP § 2144.05 part II.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
16. No claim is allowed.
17. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
18. Any inquiry concerning this communication or earlier communications from the examiner should be directed to NORA MAUREEN ROONEY whose telephone number is (571)272-9937. The examiner can normally be reached on M-F from 8:00am to 4:30pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner' s supervisor, Misook Yu, can be reached at telephone number (571) 272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/patents/uspto-automated- interview-request-air-form.
July 14, 2026
/Nora M Rooney/
Primary Examiner, Art Unit 1641
Prosecution Insights