DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/13/2026 has been entered.
Status of Application
Applicants' arguments/remarks filed 02/13/2026 are acknowledged. Claims 1, 27, 33, 37 and 43 are currently amended. Claims 44-45 are newly added. Claims 1, 20, 22-23, 25-27, 33, 36-37, and 42-45 are examined on the merits within and are currently pending .
Withdrawn Rejections
With applicants' amendment, filed 02/13/2026:
the 35 U.S.C. § 112(b) rejection of Claims 1, 33 and 43, as being indefinite has been withdrawn in view of the amendments;
the 35 U.S.C. § 103 rejection of Claims 1, 20, 22-23, 25-26, 33, 36, and 37 over Papadimitriou., and Agrawal et al., has been withdrawn in view of the amendments;
the 35 U.S.C. § 103 rejection of Claims 27 and 42-43 over Papadimitriou (AU 199944866A1). Agrawal et al. and Engler et al. has been withdrawn in view of the amendments;
Modified Rejections
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 non-obviousness.
Claim(s) 1, 20, 22-23, 25-27, 33, 36, 37 and 42-45 is/are rejected under 35 U.S.C. 103 as being unpatentable over Magagnoli et al. (CA 2542777 C) in view of Agrawal et al., (WO 2018201064 A1).
Claims 1 and 27, 37, 42 and 44-45,
Magagnoli et al. teach a method for the stabilization of the bARE class bacterial protein, compositions comprising a stabilized bARE protein, compositions comprising a substantially integral bARE class protein and immunogenic composition formulations incorporating same. (Abs). The bARE protein compositions are "stabilized" compositions. By "stabilized" is intended the compositions retain the bARE polypeptide in its substantially multimeric state during storage, and hence the therapeutic effectiveness of this bARE polypeptide is not compromised due to aggregate formation or dissociation into subunit forms. By "during storage" is intended a composition or formulation once prepared, is not immediately administered to a subject. Rather,
following preparation, it is packaged for storage, either in a liquid form, in a frozen state,
or in a dried form for later reconstitution into a liquid form or other form suitable for administration to a subject. Preferably, compositions of the invention are stored directly
in their liquid form to take full advantage of the convenience of having storage stability in
the liquid form, ease of administration without reconstitution, and ability to supply the
formulation in prefilled, ready-to-use syringes or as multidose preparations if the
formulation is compatible with bacteriostatic agents. The stabilized bARE compositions of
the invention preferably have a shelf-life of at least about 6 months, 12 months, 18
months, more preferably at least 20 months, still more preferably at least about 22 months,
most preferably at least about 24 months when stored at 2-8°C. (pg. 59 last par.-pg. 60, 1st par.).
The critical micelle concentration (CMC) of: cholamidopropyl)dimethylammonio]-1-propane sulfonate or 3-[(3-cocamidopropyl) dimethylamomonio]-1-propane sulfate, (CHAPS), Zwitterionic: 8mM.
https://www.novoprolabs.com/support/articles/detergent-types-and-critical-micelle-concentrations-cmc-202309301591.html
The stabilized composition comprising the bARE protein, arginine base at a concentration of about 150 mM to about 350 mM, and a zwitterionic agent at a concentration of from about 0.05% to about 0.5%. (pg. 27, last par.). In a preferred embodiment, the arginine base is present in the bARE composition at a concentration of about 200mM and zwitterionic agent, such as CHAPS is present at a concentration of about 0.25%. This preferred bARE composition has a pH of about 7.2. The concentration of the bARE protein or variant thereof in these compositions is about 0.01 mg/ml to about 2.0 mg/ml. (pg. 28, 1st. par.). The bARE composition may additionally comprise a solubilizing agent or solubility enhancer that contributes to the protein's solubility beyond the enhanced solubility obtained using the low-ionic-strength formulations disclosed herein. (pg. 28, 3rd par.).
Magagnoli et al. do not teach the protein is an antibody.
Agrawal et al. teach liquid pharmaceutical compositions comprising a therapeutic polypeptide, such as an antibody, (pg. 2, lines 1-2). Polypeptide formulations, comprise surfactants in appropriate amounts to prevent surface-related aggregation during freezing and drying (pg. 35, line3-6). Zwitterionic surfactants include 3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate (CHAP), CHAPSO (3-[(3-Cholamidopropyl) dimethylammonio]-2-hydroxy-1-propanesulfonate) (pg. 33, line 14) . Pharmaceutical formulations include liquid (e.g., aqueous) solutions, which can be directly administered (pg. 12, 1st par.). With liquid formulations, preservative effectiveness and stability have to be maintained over the entire product shelf-life (usually about 18 -24 months). Preservative effectiveness often needs to be demonstrated in the final formulation containing the active drug and all excipient components (pg. 36, 3r last par.). Once the pharmaceutical formulation has been formulated, it can be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or as a dehydrated or lyophilized powder. (pg. 41, 1st par.). The surfactant can be in a concentration of about 0% to about 5% w/v, such as in a concentration of at least about 0.001, 0.002, 0.004, 0.005, 0.007, 0.01, 0.05 w/v. In another example, the surfactant is incorporated in a concentration of about 0.001% to about 0.5% w/v. (pg. 33, line 21-27), with which 0.001-0.8% w/v of CHAPS or CHAPSO is lower than its CMC value in water. formulations. High concentrations of kosmotropes (e.g., >1 molar ammonium sulfate) are commonly used to precipitate polypeptides from solution (salting-out) where the kosmotrope is preferentially excluded from the polypeptide surface reducing the solubility of the polypeptide in its native conformation. Removal or dilution of the salt returns the polypeptide to solution. (pg. 34, last par.). In order to maintain isotonicity in a parenteral formulation, salt concentrations are generally limited to less than 150 mM for monovalent ion combinations. (pg. 35, last par.), which are considered to be low to moderate ionic strength.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have a protein formulation comprising a protein and at least one cholate surfactant at concentrations, CHAP with low ionic strength taught by Magagnoli et al. and Agrawal et al. and the protein is an antibody, taught by Agrawal et al. since they have proven cholate surfactant is suitable to provide stable liquid formulations prior to use for proteins and antibodies.
With regard to claim 20,
Magagnoli et al. teach the formulation of claim 1, wherein the formulation does not
comprise any polysorbate, poloxamer, or alkylglycoside surfactant. Protein LTK 63, in 0.05% chaps, Static or shaken. (pg. 85, last par. and Table 6(a) and 6(b)).
With regard to claim 22,
Magagnoli et al. teach the formulation of claim 20, wherein the formulation consists essentially of at least one cholate surfactant, at least one protein species, at least one buffer species, and at least one non-surfactant stabilizer. Protein LTK 63 in phosphate 20 mM, pH 7.4 + 200 mM arginina + CHAPS 0.05% STATIC and SHAKEN. (pg. 85, Last par. and Table 6(a) and 6(b) and pg. 86, 1st par. and Table 7(a) and pg. 87, 7(b)).
With regard to claims 23 and 25,
Agrawal et al. teach the composition of claim 88, wherein the surfactant is 0.01% (w/v) polysorbate 80 or 0.004% polysorbate 20. (pg. 60, claim 27, pg. 67, claim 90).
With regard to claim 26,
Magagnoli et al. teach the bARE composition may additionally comprise non-ionic detergents. Examples of non-ionic detergents include but are not limited to detergents containing uncharged, hydrophilic head groups that consist of either polyoxyethylene moieties such as but not limited to Brij ® and Triton® (such as for example, Triton-X, NP-40, Brij, Tween*). (pg. 28, last par.)
With regard to claims 33 and 43,
Magagnoli et al. teach LTK 63, even in presence of L-Arginine and CHAPS 0.05% shaken having no precipitates on long term shaken storage, up to 115 days (see Table 6(a).
determined by the slopes of linear fittings (Table 6(b)). (pg. 85, last par. and Table 4(a), pg. 82).
Agrawal et al. teach a formulation is considered stable when the polypeptide in the formulation retains physical stability, chemical stability and/or a biological activity. "Stable" formulations of biologically active polypeptides are formulations that exhibit 40 °C for 1 to 12 weeks; (pg. 12, lines 26-27). The most commonly used surfactants are the non-ionic fatty acid esters of sorbitan polyethoxylates--i.e., polysorbate 20 and polysorbate 80. The two differ only in the length of the aliphatic chain that imparts hydrophobic character to the molecules, C-12 and C-18, respectively. Polysorbate 80 is more surface-active and has a lower critical micellar concentration than polysorbate 20. Both polysorbate 20 and polysorbate 80 have been shown to protect against agitation-induced aggregation. Polysorbate 20 and 80 also protect against stress induced by freezing, lyophilization and reconstitution. (pg. 32, line 3-9).
With regard to claim 36,
Magagnoli et al. teach a method of stabilizing an ABS bacterial ADP-ribosylating exotoxin (bARE) class protein wherein the method comprises providing the ABS bARE class protein and combining the ABS bARE class protein with arginine and a derivative of cholesterol with a carboxylic acid. (Claim 7, pg. 91). The method according to claim 7, wherein said derivative of cholesterol is selected from 3-(3-Cholamidopropyl)-dimethylammonio-1-propanesulfonate (CHAPS) and (3-(3- Cholamidopropyl)-dimethylammonio-2-hydroxy-propanesulfonate) (CHAPSO). (Claim 8, pg. 92).
Response to Arguments
35 USC§ 103 Rejections
Claims 1, 20, 22-23, 25-26, 33, 36, and 37:
Applicants argue that both Papadimitriou and Agrawal do disclose aqueous polypeptide/protein formulations including cholate surfactants, and overlapping concentrations and conditions as in the rejected claims. Id., pages 4-11 because Papadimitriou does not teach that the protein is an antibody, but contends that Agrawal teaches "liquid pharmaceutical compositions comprising a therapeutic polypeptide, such as an antibody." A determination of obviousness also requires a reasonable expectation of success. a prima facie case of obviousness with respect to
independent claim 1 or its dependent claims 20, 22-23, 25-26, 33, 36, and 37. First, amended claim 1 part ( c) recites a formulation comprising "sodium glycocholate hydrate (SGH), at a concentration (w/v) of 0.025% to 0.05%, wherein the formulation is a high ionic strength formulation." None of the cited references teach or disclose SGH, let alone how best to use it in a protein formulation. Accordingly, none of the cited references alone or together would suggest the aqueous formation as currently claimed in claim 1 part (c).
Applicant's arguments have been fully considered and were not persuasive according to previous office action that both Papadimitriou and Agrawal were teaching claim 1, since it was the 103 rejection, that no one reference has to teach all the claim limitations for an obviousness rejection and therefore several references are combined to render the claims obvious. One with ordinary skill in the art can learn from and select specific parts of several prior arts’ teachings before the effective filing date of the invention to achieve better outcome results even though some prior arts may teach more and may teach different things. Papadimitriou does not teach antibodies and Agrawal teach antibodies. On the reasonable expectation of success, when the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to rebut the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). See also MPEP § 716.07. See also In re Antor Media Corp., 689 F.3d 1282, 103 USPQ2d 1555 (Fed. Cir. 2012). On the other hand, with the amendment that SCH is removed, Papadimitriou’s teachings are no longer applicable, so for this new office action, Prior Art Papadimitriou is removed and is substituted by a new Prior Art Magagnoli, who teaches option (a) of claim 1. Again, it is a 103 rejection with Agrawal, who teach optional liquid formulation until administration, with CHAPS, option (a), at a concentration of at least about 0.001-0.05 w/v could apply for antibodies, with low ionic strength. Agrawal specifically reciting: :In order to maintain isotonicity in a parenteral formulation, salt concentrations are generally limited to less than 150 mM for monovalent ion combinations” (pg. 35, last par.), which are considered to be low to moderate ionic strength according to Applicant’s definition in SPEC. pg. 17, 1st par.:
A high ionic strength formulation herein may have 150 mM or higher salt concentration, such as 175 mM or higher, 200 mM or higher, 250 mM or higher, 150-300 mM, 200-300 mM, 200-250 mM, 175-250 mM, or 150-250 mM.). With this definition of applicant on ionic strength, Agrawal’s teaching is applied. Also, both Magagnoli and Agrawal teach following preparation, it is packaged for storage, with option of a liquid form.
Applicants argue that with respect to claim 1, parts (a) and (b), reciting the CHAPS or BigCHAP surfactants at particular concentrations at low ionic strength, Papadimitriou provides no suggestion at all of such formulations. Instead, at best Papadimitriou at page 3, lines 15-26, provides a laundry list of surfactants that includes CHAPS among many others, Papadimitriou provides no information regarding how to use them in any antibody formulation such as that of claim 1, let alone any suggestion that they should be used at low ionic strength. Indeed, Papadimitriou only mentions CHAPS in passing in that laundry list at page 3. Similarly, Agrawal provides an even larger laundry list of possible surfactants that include many different classes of surfactants, in an over 1000-fold concentration range, with no disclosure at all as to other factors such as ionic strength. Agrawal, at page 33. Thus, this combination of references cannot teach the subject matter of either claim l(a) or claim l(b ).
Applicant's arguments have been fully considered and were not persuasive according to previous office action and also to this new office action since option (a), (b) or (c) is optional. Papadimitriou and Agrawal do not need to teach all (a), (b) and (c). Similarly, Magagnoli and Agrawal do not need to teach all (a), (b) and (c). In fact, Magagnoli and Agrawal teach option (a) with low ionic strength: Magagnoli teach using the low-ionic-strength formulations disclosed herein. (pg. 28, 3rd par.); and Agrawal teach salt concentrations are generally limited to less than 150 mM for monovalent ion combinations. (pg. 35, last par.), which are considered to be low to moderate ionic strength. Please see details of the rejection of claim 1 above.
Applicants argue that Agrawal's examples are all performed using polysorbate 80 as a surfactant.
Agrawal is focused instead on viscosity-lowering excipients like high concentrations of amino
acids and dipeptides. And, while Agrawal does not mention the ionic strength of the formulations, a person of ordinary skill in the art would reasonably expect these formulations to have elevated ionic strength, due to the high- concentration ionic salts in solubilization buffer and the viscosity-reducing excipients used in Agrawal's formulations. In other words, the generally high ionic strength formulations in Agrawal designed to address viscosity in high-protein, high-excipient solutions teach away from formulations claimed herein reciting CHAPS or Big CHAP in a low ionic strength formulation, and only STH, SGH, or SCH surfactants in a high ionic strength formulation. Thus, this combination of references cannot be used to suggest any specific liquid antibody formulation comprising the specific ingredients of the formulations of claim 1 (a) or claim 1 (b) or claim l(c) or any of their dependent claims.
Applicant's arguments have been fully considered and were not persuasive with explanation above.
Applicants argue that specifically, CHAPS and SGH at 0.05% (w/v) effectively prevented aggregation of different antibody species under harsh agitation conditions. As previously explained, the percentage of high molecular weight species (HMWS) was used to measure the proportion of aggregated forms of antibody. As shown in Examples 1 and 2 the total HMWS % for either a CHAPS-containing formulation or the SGH- containing formulation after agitation remained comparable to non-agitated controls. For example, as shown in Tables 1 and 3 the no-surfactant control samples showed significantly higher HMWS 23.13% and 65.01%, respectively as compared to around 1%-8% for the SGH-containing formulation. Similarly, Tables 2 and 4 show that both CHAPS and SGH protected antibodies from aggregation in harsh agitation conditions in a high ionic strength formulation, with levels of HMWS comparable to non-agitated control samples. Importantly, there is a significant difference in the amount of HWMS percentage formation in CHAPS- and SGH-containing solutions as compared to sodium taurocholate hydrate (STH) (2-3x more HWMS formation as compared to SGH or CHAPS). This shows the surprising effect of the CHAPS- and SGH-containing solution of those recited in the cited art. Accordingly, formulations comprising CHAPS and SGH in accordance with the claims herein effectively prevented aggregation of antibodies under these harsh conditions. It would not have been predictable in advance that this would have been the case. Accordingly, Applicant asserts that claim 1 and its dependent claims 20, 22-23, 25-26, 33, 36, and 37 are non-obvious over the cited art and Applicant respectfully requests the withdrawal of this rejection.
Applicant's arguments have been fully considered and were not persuasive since some of the antibodies of examples including agitation with CHAPS surfactant, have MW Anti-tryptase antibodies (Table 2, SPEC pg. 44) of approximately 28–36 kDa, and other up to 150kDa, while the test of formulations with antibodies are at low concentrations 1mg/ml (pg. 43, last par., pg. 44, 2nd par., pg. 46, 1st. par., pg. 49, 1st par.), while Magagnoli teach formulation of protein LTK 63 of MW around 38 kDa (LTK 63 protein MW is - Google Search), with CHAPS at 0.05% at 4mg/ml, Magagnoli et al. teach the formulation of claim 1, wherein the formulation of Protein LTK 63, in 0.05% chaps, Static or shaken. (pg. 85, last par. and Table 6(a) and 6(b)) Protein LTK 63 in phosphate 20 mM, pH 7.4 + 200 mM arginina + CHAPS 0.05% STATIC and SHAKEN. (pg. 85, Last par. and Table 6(a) and 6(b) and pg. 86, 1st par. and Table 7(a) and pg. 87, 7(b)), with applicant’s claim 1 reciting “comprising”, which does not limit additional amino acid in the formulation. Also, one with skill in the art, is known for solving the same problem, is represented with design choices, may modify the teachings of the prior arts until they can achieve better outcome results. They can modify formulations for proteins with higher molecular weights or of antibodies with additional excipients if needed from Magagnoli’s teachings.
Claims 27 and 42-43:
Applicants argue that Claim 27 recites a therapeutic protein formulation comprising a surfactant consisting essentially of CHAPS or Big CHAP at specified concentrations (0.025%-0.05%) in a low ionic strength formulation. Moreover, the formulation has not been and is not lyophilized prior to use. Such a formulation is not taught or suggested by any combination of Papadimitriou, Agrawal, and Engler. First, as noted above, Papadimitriou at best only mentions CHAPS in passing on page 3 as part of a large laundry list of possible surfactants. It certainly provides nothing to suggest preparing a formulation comprising a surfactant consisting essentially of CHAPS, within a particular concentration range of 0.025% to 0.5% and at low ionic strength, wherein the protein formulation is also not lyophilized prior to use. Agrawal similarly provides only a mere comment that "surfactants can be added ... " followed by a large laundry list of different classes of surfactants and concentration ranges well over 1000-fold. And, as noted above, Agrawal's examples are all performed using polysorbate 80 as a surfactant, while Agrawal as a whole is focused instead on viscosity-lowering excipients like high concentrations of amino acids and dipeptides. Thus, neither of these references comes even close to suggesting the very specific formulations of claim 27 and its dependent claims. Engler does not close this very broad gap between the laundry lists of Papadimitriou and Agrawal and the instant claim 27.
Applicant's arguments have been fully considered and were not persuasive according to previous office action since even though Papadimitriou only mentions CHAPS in page 3 but not within a particular concentration range of 0.025% to 0.5% and at low ionic strength, but Agrawal teaches CHAPS, at concentration 0.001-0.05, at low ionic strength. Even though Agrawal does not recite out low ionic strength, but Agrawal specifically reciting: :In order to maintain isotonicity in a parenteral formulation, salt concentrations are generally limited to less than 150 mM for monovalent ion combinations” (pg. 35, last par.), which are considered to be low to moderate ionic strength according to Applicant’s definition in SPEC. pg. 17, 1st par.:
A high ionic strength formulation herein may have 150 mM or higher salt concentration, such as 175 mM or higher, 200 mM or higher, 250 mM or higher, 150-300 mM, 200-300 mM, 200-250 mM, 175-250 mM, or 150-250 mM.).
With this definition of applicant on ionic strength, Agrawal’s teaching is applied and Engler’s and Papadimitriou’s teachings are removed. In addition, with this office action, Magagnoli teaches CHAPS at 0.05% concentration and with proteins at low ionic strength.
Conclusion
No claim is allowed.
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/NGOC-ANH THI NGUYEN/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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