DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 August 28, 2025, has been entered.
Claims 2 and 15-19 are cancelled.
Claims 1, 3-14, and 20-22 are pending and examined on the merits.
Notice Re: Prior Art Available Under Pre-AIA and 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 (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.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4-6, 8, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Murray (Molecular Genetics and Metabolism. 2015. 114: 217-225. Listed on IDS filed 8/18/23) in view of Schuchman `934 (US 2005/0153934. Previously cited), Zhou (Nature Communications. 2016. 7:13082. 10 pages), and Nyborg (Biochem. J. 2004. 381: e3-e4), and in light of Wasserstein (Molecular Genetics and Metabolism. 2015. 116: 88-97. Listed on IDS filed 8/18/23).
Murray discloses performing safety studies in which recombinant human acid sphingomyelinase (rhASM) was administered to animals (abstract; page 218, right column, last three paragraphs). According to Wasserstein, the recombinant human acid sphingomyelinase of Murray is olipudase alfa. See page 89, left column, first paragraph of Wasserstein which refers to reference number 9, which is Murray, as teaching olipudase alfa, i.e. recombinant human acid sphingomyelinase. As such, Murray meets limitations of the claimed invention by disclosing a composition comprising a recombinant human acid sphingomyelinase, wherein the composition comprises olipudase alfa.
Murray discloses that lyophilized rhASM was resuspended in sterile water prior to use (page 218, right column, second paragraph). The resulting suspension meets limitations of instant independent claim 4 since it is directed to a composition comprising a recombinant human acid sphingomyelinase, wherein the composition is an aqueous liquid composition comprising olipudase alfa.
Murray differs from the invention of instant claim 4 in that Murray does not expressly disclose that the suspension (obtained by resuspending lyophilized rhASM in water) comprises 1-10 mg/mL olipudase alfa (i.e., rhASM), 10-50 mM sodium phosphate, 70-150 mM L-methionine, and 1-10% w/v sucrose, wherein the composition has a pH of 5-8 and contains no detectable amount of mannitol or chelating agents.
Murray discloses that the vehicle control in their studies contained 20 mM sodium phosphate, 5% sucrose, 100 mM methionine, and 0.1 mM ethylenediaminetetraacetic acid, pH 6.5 (page 218, right column, second paragraph). Each of the concentrations of sodium phosphate, methionine, and sucrose of Murray fall within the ranges recited in instant claims 4 and 5. The concentrations of sodium phosphate, methionine, and sucrose of Murray meet the concentrations recited in instant claim 6. The pH of 6.5 falls within the ranges of instant claims 4 and 5, and meets the pH recited in instant claim 6.
Schuchman `934 discloses wild-type recombinant acid sphingomyelinase (ASM) as part of enzyme replacement therapy (paragraph [0025]). For lyophilization of ASM enzyme and small molecule active site-specific chaperones (ASSC) preparations, the enzyme concentration can be 0.1-10 mg/mL (paragraph [0088]). The enzyme concentration range of Schuchman `934 overlaps with the ranges recited for olipudase alfa in instant claims 4 and 5, and includes the olipudase alfa concentration of instant claim 6. Additionally, Schuchman `934 teaches that possible cryoprotectants, such as disaccharides and amino acids, can be added to the lyophilization mixture (paragraph [0088]). Buffers can also be added to the lyophilization mixture (paragraph [0088]).
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to prepare the lyophilized rhASM of Murray by including sodium phosphate, methionine, and sucrose with rhASM (i.e. olipudase alfa) and water to obtain an aqueous liquid composition comprising 20 mM sodium phosphate, 5% sucrose, 100 mM methionine, with a pH of 6.5, which is thereafter lyophilized. One of ordinary skill in the art would have been motivated to include these components with the rhASM to prepare the lyophilized rhASM of Murray because they are included in the vehicle control taught in Murray serving as the counterpart of lyophilized recombinant human acid sphingomyelinase resuspended in water, thus describing the composition of the reconstituted composition (when the lyophilized rhASM is resuspended in sterile water) in the absence of the enzyme itself. Furthermore, it would have been obvious to include sodium phosphate (which is directed to a buffer), sucrose, and methionine, in the lyophilized rhASM of Murray because Schuchman `934 teaches the inclusion of buffers and cryoprotectants such as disaccharides and amino acids in a lyophilized composition comprising acid sphingomyelinase. The composition rendered obvious by Murray in view of Schuchman `934 is directed to a composition containing no detectable amount of mannitol, meeting a claimed limitation.
Regarding the claimed limitation of the composition containing no detectable amount of chelating agents:
Zhou discloses that biological characterizations have revealed that proper function of human acid sphingomyelinase (ASM) requires zinc ions (page 2, left column, third paragraph). In particular, zinc ions are prerequisites for the two forms of ASM, an intracellular form and an extracellular secreted form (page 2, left column, third paragraph). Zhou investigated two crystal structures of recombinant human ASM, olipudase alfa, to observe how co-factor zinc ions and a product phosphocholine are coordinated by the enzyme (page 2, left column, second-to-last paragraph; page 2, right column, first paragraph for defining the enzyme as olipudase alfa). Zinc binding in the active site was observed, in which two neighboring zinc ions were identified in the center of the cleft of the catalytic domain (page 4, right column, second and third paragraphs). The human ASM structures reported in Zhou illustrate how the co-factor zinc ions activate the enzyme (page 6, left column, first paragraph).
Nyborg discloses that EDTA is a very potent zinc-chelating agent (abstract).
Though the vehicle control of Murray includes EDTA (directed to a chelating agent), before the effective filing date of the claimed invention, one of ordinary skill in the art would have been motivated to exclude EDTA when preparing the lyophilized rhASM rendered obvious by Murray and Schuchman `934. One of ordinary skill in the art would have been motivated to do this because human acid sphingomyelinase, including recombinant human acid sphingomyelinase (i.e., olipudase alfa), require zinc ions for its proper function, as indicated in Zhou. Since EDTA is a potent zinc-chelating agent according to Nyborg, then the skilled artisan would have expected that it would have been desirable to omit EDTA for the composition of rendered obvious by Murray and Schuchman `934 to ensure that the zinc binding to the active site of the rhASM is not interfered. Additionally, it would have been obvious to the person ordinary skill in the art to exclude EDTA because Schuchman `934 does not disclose EDTA or any other chelating agent amongst the materials for lyophilization of acid sphingomyelinase (paragraph [0088]). Therefore, Murray in view of Schuchman `934, Zhou, and Nyborg renders obvious a composition containing no detectable amount of chelating agents.
Further still, it would have been obvious to include the rhASM (i.e., olipudase alfa) in an amount such that the concentration of rhASM in the suspension (aqueous liquid composition) rendered obvious by Murray, Schuchman `934, Zhou, and Nyborg is 0.1-10 mg/mL (overlapping the ranges of instant claims 4 and 5 and including the concentration of olipudase alfa of instant claim 6, thereby rendering obvious the claimed olipudase alfa concentrations). One of ordinary skill in the art would have been motivated to do this because Schuchman `934 teaches that the enzyme can be in that concentration range for the lyophilization of acid sphingomyelinase – thus the skilled artisan would have expected that enzyme concentration range as suitable for the suspension of Murray.
Additionally, it would have been obvious to include L-methionine as the methionine in the composition rendered obvious by Murray, Schuchman `934, Zhou, and Nyborg because it would have been a matter of simple substitution of one known form of methionine for another for the predictable result of providing an amino acid for lyophilization of acid sphingomyelinase as taught in Schuchman `934 (paragraph [0088]).
As such, Murray in view of Schuchman `934, Zhou, and Nyborg (in light of Wasserstein, cited as evidence) renders obvious instant claims 4-6, as well as instant claims 8 (the lyophilized composition rendered obvious the references) and 9.
Regarding instant claim 1, the lyophilized rhASM rendered obvious by Murray, Schuchman `934, Zhou, and Nyborg (in light of Wasserstein, cited as evidence) meets claimed limitations since it is directed to a composition comprising a recombinant human acid sphingomyelinase, wherein the composition is a lyophilized composition comprising olipudase alfa, sodium phosphate, L-methionine, and sucrose. The references differ from instant claim 1 in that they do not expressly disclose the claimed concentrations: 4-7% w/w olipudase alfa, 3-7% w/w sodium phosphate, 15-25% w/w L-methionine, and 65-75% w/w sucrose. However, it would have been an obvious matter of routine optimization to vary the concentrations of the rhASM (i.e. olipudase alfa), sodium phosphate, L-methionine, and sucrose in the lyophilized rhASM rendered obvious by Murray, Schuchman `934, Zhou, and Nyborg, including varying to the concentrations of instant claim 1, so that the rhASM is sufficiently protected in its lyophilized form; the concentrations of each of the rhASM (i.e. olipudase alfa) and the additional components relative to one another would have been recognized by the skilled artisan as results-effective parameters, the result being the stabilization of the rhASM in its lyophilized form. It is noted that “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Thus instant claim 1 is rendered obvious.
Claims 3 and 10-14 are rejected under 35 U.S.C. 103 as being unpatentable over Murray, Schuchman `934, Zhou, Nyborg, and Wasserstein as applied to claims 1, 4-6, 8, and 9 above, and further in view of Schuchman `559 (US 2011/0052559. Previously cited) and Given (US 2007/0232671. Previously cited).
As discussed above, Murray in view of Schuchman `934, Zhou, and Nyborg (in light of Wasserstein, cited as evidence) renders obvious claims 1, 4-6, 8, and 9.
The references differ from claim 3 in that they do not expressly disclose a lyophilized composition consisting essentially of 5.5% w/w olipudase alfa (i.e. rhASM), 2.3% w/w sodium phosphate dibasic heptahydrate, 2.6% w/w sodium phosphate monobasic monohydrate, 20.5% w/w L-methionine, and 68.6% w/w sucrose.
The references differ from claim 10 in that they do not disclose a vial containing a lyophilized composition consisting essentially of 21.2 mg olipudase alfa (i.e. rhASM), 9.0 mg sodium phosphate dibasic heptahydrate, 10.0 mg sodium phosphate monobasic monohydrate, 79 mg L-methionine, and 265 mg sucrose. The references differ from claim 14 in that they do not expressly disclose an article of manufacture comprising the vial of claim 10 and a vial containing sterile water, 0.9% sodium chloride, or phosphate-buffered saline for reconstituting the lyophilized composition.
The references differ from claim 11 in that they do not disclose an aqueous liquid composition obtained by reconstituting a lyophilized composition consisting essentially of 21.2 mg olipudase alfa (i.e. rhASM), 9.0 mg sodium phosphate dibasic heptahydrate, 10.0 mg sodium phosphate monobasic monohydrate, 79 mg L-methionine, and 265 mg sucrose, in 5.1 mL of sterile water.
The references differ from claim 12 in that they do not disclose a vial containing a lyophilized composition consisting essentially of 4.8 mg olipudase alfa (i.e. rhASM), 2.0 mg sodium phosphate dibasic heptahydrate, 2.3 mg sodium phosphate monobasic monohydrate, 17.9 mg L-methionine, and 60 mg sucrose.
The references differ from claim 13 in that they do not disclose an aqueous liquid composition obtained by reconstituting a lyophilized composition consisting essentially of 4.8 mg olipudase alfa, 2.0 mg sodium phosphate dibasic heptahydrate, 2.3 mg sodium phosphate monobasic monohydrate, 17.9 mg L-methionine, and 60 mg sucrose, in 1.1 mL of sterile water.
Regarding instant claims 10, 12, and 14, Schuchman `559 discloses a pharmaceutical product comprising a unit dosage form of acid sphingomyelinase (ASM) in an appropriate vessel or container, such as a glass vial (paragraph [0178]). In some embodiments, the unit dosage form is a lyophilized form of ASM, and under those circumstances, the pharmaceutical product may contain a second container with sterile saline or sterile water for reconstituting the lyophilized form of ASM (paragraph [0178]). Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to provide the lyophilized rhASM rendered obvious by Murray in view of Schuchman `934, Zhou, and Nyborg (in light of Wasserstein, cited as evidence) in a first vial, and further provide sterile water in a second vial. One of ordinary skill in the art would have been motivated to do this to facilitate reconstituting the lyophilized rhASM, as supported by the teaching of Schuchman `559.
Further still, Given discloses a buffer agent mixture such as sodium phosphate monobasic monohydrate and sodium phosphate dibasic anhydrous to improve drug stability in tablets of a drug (paragraph [0088]). Also, Given teaches a lyophilized powder comprising sodium phosphate dibasic heptahydrate and sodium phosphate monobasic monohydrate (paragraph [0134]).
Before the effective filing date of the claimed invention, it would have been obvious to substitute the sodium phosphate with a mixture of sodium phosphate dibasic heptahydrate and sodium phosphate monobasic monohydrate in the lyophilized rhASM composition rendered obvious by Murray in view of Schuchman `934, Zhou, and Nyborg (in light of Wasserstein) in further view of Schuchman `559. It would have been a matter of simple substitution of sodium phosphate with other sodium phosphates for the predictable result of buffering the composition to obtain the desired pH of 6.5. There would have been a reasonable expectation of buffering the composition with a mixture of sodium phosphate dibasic heptahydrate and sodium phosphate monobasic monohydrate since Given teaches a buffer agent mixture of specifically sodium phosphate dibasic heptahydrate and sodium phosphate monobasic monohydrate for a lyophilized formulation.
Further still, it would have been a matter of routine optimization to vary the concentrations and amounts of the rhASM (i.e. olipudase alfa), sodium phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate, L-methionine, and sucrose in the lyophilized rhASM composition rendered obvious by Murray in view of Schuchman `934, Zhou, and Nyborg (in light of Wasserstein) in further view of Schuchman `559 and Given, specifically to the concentrations recited in instant claim 3, the amounts recited in instant claim 10 in the first vial, and the amounts recited in instant claim 12 in the first vial, so that the rhASM is sufficiently protected in its lyophilized form; the concentrations of each of the rhASM and the additional components relative to one another would have been recognized by the skilled artisan as results-effective parameters, the result being the stabilization of the rhASM in its lyophilized form. It is noted that “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Additionally, it would have been obvious to include the sodium phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate, L-methionine, and sucrose as the only additional components since it would have been obvious to include any combination of the agents recognized in the references for a lyophilized formulation. Therefore, instant claims 3, 10, 12, and 14 (sterile water) are rendered obvious.
Additionally, it would have been a matter of routine optimization to vary the amount of sterile water, including to 5.1 mL and 1.1 mL of sterile water, that is added respectively to the lyophilized rhASM composition of instant claims 10 and 12 rendered obvious by references, since the amount of the sterile water would have affected the degree of reconstitution of the composition and the concentrations of each of the rhASM and the additional components in the resulting reconstituted composition (directed to an aqueous liquid composition obtained by reconstituting a lyophilized composition). The amount of sterile water necessary for reconstitution would have varied depending on the total amount of lyophilized composition. Therefore, instant claims 11 and 13 are rendered obvious.
Claims 7 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Murray, Schuchman `934, Zhou, Nyborg, and Wasserstein as applied to claims 1, 4-6, 8, and 9 above, and further in view of Jalkanen (US 2017/0246254. Previously cited).
As discussed above, Murray in view of Schuchman `934, Zhou, and Nyborg (in light of Wasserstein, cited as evidence) renders obvious claims 1, 4-6, 8, and 9. The references differ from claim 7 in that they do not expressly disclose that the aqueous liquid composition further comprises 0.005% w/v polysorbate 80. The references differ from claim 20 in that they do not expressly disclose that the lyophilized rhASM (directed to the claimed lyophilized composition) comprises no more than 0.1%, 0.2%, 0.3%, 0.4%, or 0.5% moisture.
Jalkanen discloses a pharmaceutical formulation in a lyophilized form, which comprises pharmacologically effective amount of interferon beta-1a (abstract), which is a protein based pharmaceutical (paragraph [0003]). The lyophilized formulation comprises interferon beta-1a as the active ingredient; a bulking agent which can be sucrose; disodium phosphate dihydrate, sodium dihydrogen phosphate dihydrate, trisodium citrate dihydrate, and any combination thereof as a buffering agent; a surfactant which can be polysorbate; and methionine as an antioxidant (paragraphs [0060]-[0065]). In one embodiment to the invention, the lyophilized formulation comprises 50-80 weight-% of disaccharides (e.g. sucrose) per vial, based on the total weight of the lyophilized formulation (paragraph [0047]). Jalkanen also teaches that the lyophilized formulation is prepared from an aqueous solution having a pH of 5.5-7.5 comprising the components (paragraphs [0072]-[0077]).
Jalkanen indicates that non-ionic surfactants such as polysorbate are used for both preventing surface adsorption and as stabilizers against protein aggregation (paragraph [0044]). The surfactant is especially needed to prevent loss of INF-beta 1a during freeze-drying and reconstitution (paragraph [0044]). The polysorbate in Jalkanen can be polysorbate 80, and in one embodiment, the lyophilized formulation comprises 0.9-2 weight-% of the surfactant, e.g. polysorbate, based on the total weight of the lyophilized formulation (paragraph [0045]).
Also, Jalkanen teaches that the content of residual moisture of their lyophilized formulation may not be more than 5% by weight for promoting storage stability of the lyophilized formulation (paragraph [0059]).
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to include polysorbate 80 in the lyophilized rhASM composition rendered obvious by Murray in view of Schuchman `934, Zhou, and Nyborg (in light of Wasserstein, cited as evidence) (see rejection of instant claim 4) since it would have prevented loss of rhASM (i.e. olipudase alfa) during freeze-drying and reconstitution given that it had these effects on another protein (as in Jalkanen) in a lyophilized formulation. Additionally, it would have been a matter of routine optimization to vary the concentration of polysorbate 80 in the lyophilized composition, including to a concentration of 0.005% w/v, since the skilled artisan would have expected that the concentration of the polysorbate 80 is a results-effective parameter, specifically affecting the stabilization of rhASM during lyophilization and reconstitution. Therefore, instant claim 7 is rendered obvious.
Also, before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to have adjusted the residual moisture of the lyophilized rhASM rendered obvious by Murray in view of Schuchman `934, Zhou, and Nyborg (in light of Wasserstein) (see rejection of instant claim 1) to not more than 5% by weight, which necessarily includes residual moisture falling in the ranges of no more than 0.1%, 0.2%, 0.3%, 0.4%, or 0.5%, since doing so would have promoted storage stability of the lyophilized rhASM, based on the teaching for lyophilization of another protein in Jalkanen. Therefore, instant claim 20 is rendered obvious.
Claims 21 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Murray, Schuchman `934, Zhou, Nyborg, Wasserstein, Schuchman `559, and Given as applied to claims 3 and 10-14 above, and further in view of Jalkanen (US 2017/0246254. Previously cited).
As discussed above, Murray in view of Schuchman `934, Zhou, and Nyborg (in light of Wasserstein, cited as evidence) and in further view of Schuchman `559 and Given renders obvious claims 3 and 10-14. The references differ from claims 21 and 22 in that they do not expressly disclose that the lyophilized rhASM (directed to the claimed lyophilized composition) comprises no more than 0.1%, 0.2%, 0.3%, 0.4%, or 0.5% moisture.
Jalkanen discloses a pharmaceutical formulation in a lyophilized form, which comprises pharmacologically effective amount of interferon beta-1a (abstract), which is a protein based pharmaceutical (paragraph [0003]). The lyophilized formulation comprises interferon beta-1a as the active ingredient; a bulking agent which can be sucrose; disodium phosphate dihydrate, sodium dihydrogen phosphate dihydrate, trisodium citrate dihydrate, and any combination thereof as a buffering agent; a surfactant which can be polysorbate; and methionine as an antioxidant (paragraphs [0060]-[0065]). In one embodiment to the invention, the lyophilized formulation comprises 50-80 weight-% of disaccharides (e.g. sucrose) per vial, based on the total weight of the lyophilized formulation (paragraph [0047]). Jalkanen also teaches that the lyophilized formulation is prepared from an aqueous solution having a pH of 5.5-7.5 comprising the components (paragraphs [0072]-[0077]).
Also, Jalkanen teaches that the content of residual moisture of their lyophilized formulation may not be more than 5% by weight for promoting storage stability of the lyophilized formulation (paragraph [0059]).
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to have adjusted the residual moisture of the lyophilized rhASM rendered obvious by Murray in view of Schuchman `934, Zhou, and Nyborg (in light of Wasserstein) and further in view of Schuchman `559 and Given (see rejection of instant claims 10 and 12) to not more than 5% by weight, which necessarily includes residual moisture falling in the ranges of no more than 0.1%, 0.2%, 0.3%, 0.4%, or 0.5%, since doing so would have promoted storage stability of the lyophilized rhASM, based on the teaching for lyophilization of another protein in Jalkanen. Therefore, instant claims 21 and 22 are rendered obvious.
Response to Arguments
After further consideration, the rejections under 35 U.S.C. 103 of the last Office Action have been withdrawn. In particular, the rejections withdrawn are the rejection under 35 U.S.C. 103 of claims 1, 4-9, and 20 as being unpatentable over McGovern in view of Murray, Schuchman `934, and Jalkanen, and the rejection under 35 U.S.C. 103 of claims 3, 10-14, 21, and 22 as being unpatentable over McGovern, Murray, Schuchman `934, and Jalkanen in further view of Schuchman `559 and Given.
However, new grounds of rejection under 35 U.S.C. 103 are set forth over the same previously cited references in combination with the newly cited references Zhou, Nyborg, and Wasserstein.
Applicant’s arguments filed August 28, 2025, are unpersuasive with respect to the new grounds of rejection. Applicant cites Exhibit 2, which is a label of Xenpozyme® (olipudase alfa), for describing the drug substance and showing that the commercial drug, a lyophilized composition, contains all the ingredients recited in claim 1 and does not contain chelating agents. Applicant asserts that this information indicates that chelating agents are not desired components of lyophilized olipudase alfa compositions. Though Exhibit 2 does disclose the claimed composition in which chelating agents are absent, there is no teaching in Exhibit 2 stating that chelating agents are not desired, nor is there any reasoning provided in Exhibit 2 to explain why chelating agents are undesired. Exhibit 2 is not evidence demonstrating unexpected results (e.g., superiority in a characteristic to an unexpected extent) for the lyophilized composition containing no chelating agents as compared to the lyophilized composition containing at least one chelating agent.
Additionally, Applicant provides Exhibits 3 and 4 which are the two references in footnote 1 on page 11 of the Remarks filed April 10, 2025. Applicant cites these references as evidence that some enzymes (e.g., trypsin and clostripain) need chelating agents in their formulations to maintain biological activity. Therefore, Applicant asserts that a skilled artisan would not have found it obvious to remove a chelating agent from the formulation of Murray. Instead, Applicant argues that the person would have been led away from Murray from excluding chelating agents when formulating olipudase alfa (arguments on page 11 of Remarks filed April 10, 2025). Exhibit 3 states that EDTA, a chelating agent, is often added to trypsin solutions to enhance enzymatic activity by neutralizing calcium and magnesium ions that enhance cell-to-cell adhesion and obscure the peptide bonds on which trypsin acts (first page, left column, second paragraph). Exhibit 4 indicates Co2+, Cu2+, Cd2+, and heavy metal ions as inhibitors of clostripain (first page, Inhibitors section).
However, the evidence of Exhibits 3 and 4 are specific to trypsin and clostripain, and do not speak to the effect of EDTA or metal ions on the activity of olipudase alfa. Instead, the newly cited reference Zhou teaches that zinc ions are required for the proper function of human acid sphingomyelinase (page 2, left column, third paragraph). Based on that teaching, the skilled artisan would have been motivated to exclude a chelating agent such as EDTA in a formulation of olipudase alfa since a chelating agent would have been expected to chelate zinc ions necessary for the proper function of the enzyme. Additionally, Qiu (Journal of Biological Chemistry. 2003. 278(35): 32744-32752) investigated metal dependence of recombinant human acid sphingomyelinase (rhASM) activity, finding that in the absence of metal ions, both forms of rhASM have rather low activity, and divalent metal ions such as Mg2+ and Ca2+ have little effect on the activity of either form of the enzyme (page 32747, right column, first paragraph). Thus, the neutralization of calcium and magnesium ions by EDTA is not necessary for the enzymatic activity of rhASM (i.e., olipudase alfa), which is different in the case of trypsin activity (Exhibit 3).
Conclusion
No claims are allowed.
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/SUSAN E. FERNANDEZ/Examiner, Art Unit 1651