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 .
Withdrawal of Rejections
The response and amendments filed on 02/20/2026 are acknowledged. Any previously applied minor objections and/or minor rejections (i.e., formal matters), not explicitly restated here for brevity, have been withdrawn necessitated by Applicant’s formality correction and/or amendments. For the purposes of clarity of the record, the reasons for the Examiner’s withdrawal, and/or maintaining, if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner’s Response to Arguments section.
Briefly, the previous claims rejections under 35 U.S.C. 112(b) for indefiniteness have been withdrawn necessitated by Applicant’s amendments; however, new grounds of rejection are set forth below. The previous claim rejections under 35 U.S.C 112(a) for written description have been withdrawn necessitated by Applicant’s amendments. The previous claim rejections under 35 U.S.C 103 for obviousness have been withdrawn necessitated by Applicant’s amendments; however, new grounds of rejection are set forth below.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
New Grounds of Rejection Necessitated by Amendments
Claim Rejections - 35 USC § 112(b), Indefiniteness
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 14, 16, and 88-89 are rejected under 35 U.S.C. 112(b) 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.
Claims 14 and 16 recite “…the first optimal pH is between about 5.5 and about 7.5…” and “…the third optimal pH is between about 5.5 and about 7.5…”, respectively; however, the highest and lowest values of the pH range are unclear. The instant specification defines “about” as “referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1% from the specified value” (see, e.g., instant specification, [0107]). If the variation is ±20%, this would result in the lowest pH value for the first and third optimal pH’s to be either 4.4 (i.e., -20% of 5.5) or 6.6 (i.e., +20% of 5.5) , and the highest pH value to be either 6.0 (i.e., -20% of 7.5) or 8.0 (i.e., +20% of 7.5). Therefore, the lowest pH value and the highest pH value can overlap and/or be the same, which makes it unclear what the exact limits are to the claimed pH range. Moreover, based off the definition of “about” in the instant specification, the lowest pH value can actually be higher than the highest pH value in the claimed range; therefore, range of the claimed pH’s is unclear for the first and third optimal pH’s; i.e. can it be the same and still be 1st and 3rd.
Claims 14 and 16 recite “…the first optimal salt concentration is not more than about 100 mM…” and “…the third optimal salt concentration is not more than about 100 mM…”, respectively; however, the highest salt concentration is unclear. As stated above, the instant specification defines “about” as “referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1% from the specified value” (see, e.g., instant specification, [0107]). If the variation is ±20%, this would result in the highest salt concentration being either 80 mM (i.e., -20% of 100 mM), 120 mM (i.e., +20% of 100 mM), or between 80-120 mM. Therefore, the first and third optimal salt concentrations can overlap and/or can be the same; therefore, it is unclear how the first and third optimal salt concentrations differ from each other within the claimed invention; i.e. is it the same.
Claims 88 and 89 recite “the first optimal salt concentration is between about 5 mM and about 100 mM” and “the third optimal salt concentration is between about 1 mM and about 100 mM”, respectively; however, the lowest and highest salt concentrations for these ranges is unclear. As stated above, the instant specification defines “about” as “referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1% from the specified value” (see, e.g., instant specification, [0107]). If the variation is ±20%, this would result in the lowest salt concentration for the first optimal salt concentration to be either 4 mM (i.e., -20% of 5 mM), 6 mM (i.e., +20% of 5 mM), or between 4 mM and 6 mM, while the highest salt concentration for the first optimal salt concentration would be either 80 mM (i.e., -20% of 100 mM), 120 mM (i.e., +20% of 100 mM), or between 80 mM and 120 mM. Moreover, based on this, the lowest third optimal salt concentration would be either 0.8 mM (i.e., -20% of 1 mM), 1.2 mM (i.e., +20% of 1 mM), or between 0.8 and 1.2 mM, while the highest salt concentration for the third optimal salt concentration would be either 80 mM (i.e., -20% of 100 mM), 120 mM (i.e., +20% of 100 mM), or between 80 mM and 120 mM. Therefore, the first and third salt concentrations can overlap and/or be the same, which makes it unclear what the limits are to the claimed salt concentration range; i.e. is it the same. Moreover, since the first and third salt concentrations can overlap and/or be the same, it is unclear how these salt concentrations differ from each other within the claimed invention.
New Grounds of Rejection Necessitated by Amendments
Claim Rejections - 35 USC § 103, Obviousness
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 5, 9, 11, 14, 18, 22, 26, 46, 85-86, and 88 are rejected under 35 U.S.C. 103 as being unpatentable over Kim (US 2002/0137173; Date of Publication: September 26, 2002 – cited in the IDS filed on 09/24/2025 – previously cited) in view of Yang (WO 2019/227029; Date of Publication: November 28, 2019 – cited in the IDS filed on 09/24/2025 – previously cited).
Kim’s general disclosure relates to “a sphingomyelinase derived from the neuron membrane of the bovine brain, which is 60 kDa in molecular weight and Mg2+-dependent in activity with an optimal pH ranging from 6.0 to 9.0 (see, e.g., Kim, abstract). Moreover, Kim discloses purification methods for isolating the sphingomyelinase from cells, such as “subjecting the supernatant to hydrophobic interaction chromatography, anion exchange high-performance liquid chromatography, hydrophobic interaction high performance liquid chromatography, and cation exchange fast protein liquid chromatography” (see, e.g., Kim, abstract).
Regarding claims 1, 26, and 46 pertaining to step (i), Kim teaches “a method for isolating the sphingomyelinase according to the present invention, comprising the steps of: homogenizing a bovine brain tissue and centrifuging the homogenate to remove cell debris and nuclei; separating cell membranes from the supernatant into a pellet through centrifugation; treating the cell membrane pellet with a buffer containing ammonium sulfate to disassociate the sphingomyelinase from the membrane; subjecting the extract to anion exchange chromatography; sonicating the chromatography fraction in a buffer containing Triton X-100 and centrifuging the sonicated fraction to obtain a supernatant containing the sphingomyelinase; and purifying the sphingomyelinase by subjecting the supernatant to hydrophobic interaction chromatography, anion exchange high-performance liquid chromatography, hydrophobic interaction high performance liquid chromatography, and cation exchange fast protein liquid chromatography, in due order” (see, e.g., Kim, [0013]). Furthermore, Kim teaches within Example 1, step 6, that the sphingomyelinase was eluted from the cation exchange chromatography column and collected for subsequent analysis of activity for the purified protein (see, e.g., Kim, [0064]).
Regarding claim 5 pertaining to subjecting the protein mixture to one or more purification columns, Kim teaches within Example 1 that the sphingomyelinase mixture is subjected to DEAE-Cellulose anion exchange chromatography, hydrophobic interaction chromatography, anion exchange HPLC, and hydrophobic interaction HPLC before cation exchange chromatography (see, e.g., Kim, Example 1, [0050]-[0064]).
Regarding claim 11 pertaining to the cation exchange chromatography resin, Kim teaches a Mono S cation exchange FPLC column (see, e.g., Kim, [0064]), which has a sulfonate group.
Regarding claims 22, 26, and 46 pertaining to the rASM isoforms, Kim teaches that ASM can dimerize, or aggregate (see, e.g., Kim, [0039]). Moreover, since ASM can dimerize, one of ordinary skill in the art would expect that the ASM composition would comprise both unmodified ASM isoforms and dimerized ASM isoforms based on the percentage of dimerization. Additionally, the Examiner has interpreted the phrase “optionally” in claim 22, to mean that the subsequent limitations are not required, or necessary, as part of the claimed invention.
Regarding claim 86 pertaining to the temperature, Kim teaches purification of the sphingomyelinase partially at 4oC (see, e.g., Kim, Example 1), which is approaching the instantly claimed range (see, e.g. MPEP 2144.05(I)).
Regarding claims 14 and 88 pertaining to the CEX chromatography wash buffer, Kim teaches washing the FPLC column with “buffer S”, which comprises 25 mM sodium acetate pH 6.5 and 1 mM EDTA (see, e.g., Kim, [0042]).
However, Kim does not teach: a recombinant acid sphingomyelinase (claim 1); or wherein the protein mixture is obtained from Chinese Hamster Ovary (CHO) cells expressing the rASM (claim 9); or wherein the purified rASM preparation has a specific activity of about 5 to 50 U/mg (claim 18); or wherein the purified rASM is buffer exchanged (claim 85).
Yang’s general disclosure relates to composition comprising a recombinant human acid sphingomyelinase in order to treat patients who are deficient in acid sphingomyelinase (see, e.g., Yang, abstract). Moreover, Yang discloses a recombinant human acid sphingomyelinase (rASM) produced in Chinese Hamster Ovary (CHO) cells (see, e.g., Yang, [0036]), and further discloses that composition comprising rASM derived from CHO cells have superior stability in lyophilized compositions during long term storage (see, e.g., Yang, [0051]).
Regarding claims 1 and 9 pertaining to a recombinant acid sphingomyelinase (rASM), Yang teaches a recombinant human acid sphingomyelinase (see, e.g., Yang, abstract), wherein the rASM is olipudase alfa, which “is the glycoform alpha of a human ASM (EC-3.1.4.12) produced in CHO cells” (see, e.g., Yang, [0036]). Moreover, Yang teaches that the rASM can dimerize and the degree of dimerization can be measured by size exclusion HPLC or protein gel (see, e.g., Yang, [0039]). Additionally, the Examiner has interpreted the phrase “optionally” in claim 8, to mean that the subsequent limitations are not required, or necessary, as part of the claimed invention.
Regarding claim 18 pertaining to the specific activity, Yang teaches that the rASM has a specific activity of 11-42 U/mg (see, e.g., Yang, [0090]). Additionally, the Examiner has interpreted the phrase “optionally” in claim 18, to mean that the subsequent limitations are not required, or necessary, as part of the claimed invention.
Regarding claim 85 pertaining to buffer exchange, Yang teaches “human ASM and desired excipients may be added to, or buffer-exchanged into, a sodium phosphate buffer with the desired sodium phosphate concentration and pH” (see, e.g., Yang, [0049]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to perform Kim’s purification methods on a sphingomyelinase, wherein the sphingomyelinase is a recombinant human sphingomyelinase obtained from CHO cells, as taught by Yang. One would have been motivated to do so because Yang teaches that CHO cells can produce rASM, with or without certain modifications relative to the wildtype sequence and can demonstrate superior stability (see, e.g., Yang, [0035], [0039]). Additionally, Yang teaches that rASM derived from CHO cells have superior stability in lyophilized compositions during long term storage (see, e.g., Yang, [0051]). Moreover, Kim teaches methods of purifying sphingomyelinase from bovine brains (see, e.g., Kim, [0035], [0037]) by subjecting the supernatant to hydrophobic interaction chromatography, anion exchange high-performance liquid chromatography, hydrophobic interaction high performance liquid chromatography, and cation exchange fast protein liquid chromatography, in due order (see, e.g., Kim, abstract). Therefore, based on the teachings of Kim and Yang, it would have been obvious to perform Kim’s sphingomyelinase purification methods on Yang’s rhASM in order to obtain purified rhASM. One would have been motivated to do so because Kim and Yang both teach compositions and methods comprising sphingomyelinase.
Claims 2, 6, 12, 16, and 89 are rejected under 35 U.S.C. 103 as being unpatentable over Kim and Yang as applied to claims 1, 5, 9, 11, 14, 18, 22, 26, 46, 85-86, and 88 above, and further in view of Falkenstein (U.S. Patent Number 9,481,706; Date of Publication: November 1, 2016 – cited in the IDS filed on 09/24/2025- previously cited).
The teachings of Kim and Yang, herein referred to as modified-Kim-Yang, are discussed above as it pertains to purifying rASM.
However, modified-Kim-Yang does not teach: wherein the protein mixture is subject to an IMAC and a CEX chromatography in tandem, and eluate obtained from the IMAC is subjected to the CEX chromatography (claim 2); a step to concentrate the purified rASM (claim 6); or wherein the IMAC comprises a chelating resin (claim 12).
Falkenstein’s general disclosure relates to “a method for the purification of a not-glycosylated, heterologous polypeptide, which has been recombinantly produced in a prokaryotic cell, wherein the method comprises three chromatography steps of which the first chromatography step selected from i) hydrophobic charge induction chromatography, or ii) hydrophobic interaction chromatography, or iii) affinity chromatography, or iv) ion exchange chromatography, the second chromatography step is selected from i) anion exchange chromatography, or ii) cation exchange chromatography, or iii) hydroxylapatite chromatography, or iv) hydrophobic interaction chromatography, and the a third chromatography step is selected from i) hydrophobic charge induction chromatography, or ii) anion exchange chromatography, or iii) cation exchange chromatography, or iv) hydrophobic interaction chromatography, whereby the first chromatography step is an affinity chromatography in case of polypeptides capable of interacting with metal ligands, the second chromatography step is not a hydroxylapatite chromatography step in case of polypeptides with an isoelectric point below 6.0, and the third chromatography step can be performed in flow-through mode with polypeptides having a low or high isoelectric point” (see, e.g., Falkenstein, abstract).
Regarding claim 2 pertaining to the chromatography steps, Falkenstein teaches a first chromatography step that can be IMAC, followed by a second chromatography step, which can be CEX (see, e.g., Falkenstein, abstract & “Summary of the Invention”, lines 27-47). Therefore, one of ordinary skill in the art would understand that the protein mixture is subjected to IMAC and CEX chromatography in tandem.
Regarding claim 6 pertaining to a step to concentrate the purified rASM, Falkenstein teaches a third chromatography step, which is performed after IMAC and CEX chromatography, respectively, and consists of subjecting the purified rASM flow-through (i.e., eluate) to a “chromatography step selected from i) hydrophobic charge induction chromatography, ii) anion exchange chromatography, iii) cation exchange chromatography, or iv) hydrophobic interaction chromatography” in order to concentrate the polypeptide solution (see, e.g., Falkenstein, pg. 18, col. 10, lines 1-38).
Regarding claim 12 pertaining to the IMAC chelating resin, Falkenstein teaches chelating metals for the IMAC, such as copper, nickel, or zinc (see, e.g., Falkenstein, pg. 16, col. 6, lines 21-26). Additionally, the Examiner has interpreted the phrase “optionally” in claim 12, to mean that the subsequent limitations are not required, or necessary, as part of the claimed invention.
Regarding claims 16 and 89 pertaining to the IMAC wash buffer, Falkenstein teaches in Example 5 that metal chelating chromatography (i.e., IMAC) comprising a copper chelating Sepharose resin was loaded with interferon protein and washed with 50 mM acetic acid supplemented with 100 mM sodium chloride (i.e., salt), adjusted to a pH of 4.95 (see, e.g., Falkenstein, Example 5) (see, e.g., MPEP 2144.05(I)). Additionally, the Examiner has interpreted the phrase “optionally” in claim 16, to mean that the subsequent limitations are not required, or necessary, as part of the claimed invention.
It would have been first obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to perform modified-Kim-Yang’s purification methods for a sphingomyelinase, wherein the method comprises subjecting the protein mixture to an IMAC and a CEX chromatography in tandem, wherein the IMAC resin is copper, nickel, or zinc, as taught by Falkenstein. One would have been motivated to do so because Falkenstein teaches that affinity chromatography that uses metal chelators within the resin is effective at binding polypeptides with histidine tags, or other polypeptides depending on the specificity of the chromatographical functional group, which allows for specificity when binding polypeptides (see, e.g., Falkenstein, pg. 16, col. 5, lines 55-67 & col. 6, lines 1-11). Moreover, modified-Kim-Yang teaches sphingomyelinase mixture is subjected to DEAE-Cellulose anion exchange chromatography, hydrophobic interaction chromatography, anion exchange HPLC, and hydrophobic interaction HPLC before cation exchange chromatography (see, e.g., Kim, Example 1, [0050]-[0064]). Therefore, based on the teachings of modified-Kim-Yang and Falkenstein, it would have been obvious to purify sphingomyelinase by subjecting the protein mixture to an IMAC and a CEX chromatography in tandem. One would have expected success because modified-Kim-Yang and Falkenstein both teach purification methods for proteins.
It would have been secondly obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to perform modified-Kim-Yang’s purification methods for a sphingomyelinase, wherein the protein is concentrated after IMAC and CEX chromatography, as taught by Falkenstein. One would have been motivated to do so because Falkenstein teaches that hydrophobic charge induction chromatography or anion exchange chromatography can be performed “in flow-through mode with polypeptides having a low or high isoelectric point” to concentrate the polypeptide solution (see, e.g., Falkenstein, pg. 18, col. 10, lines 1-38). One of ordinary skill in the art would readily understand that concentrating the solution will provide one with increased concentration of the protein(s) of intertest, while decreasing the amount of unwanted proteins. Moreover, modified-Kim-Yang teaches purifying the sphingomyelinase by subjecting the supernatant to hydrophobic interaction chromatography, anion exchange high-performance liquid chromatography, hydrophobic interaction high performance liquid chromatography, and cation exchange fast protein liquid chromatography, in due order” (see, e.g., Kim, [0013]). Therefore, based on the teachings of modified-Kim-Yang and Falkenstein, it would have been obvious to concentrate the sphingomyelinase protein solution by performing
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Kim and Yang as applied to claims 1, 5, 9, 11, 14, 18, 22, 26, 46, 85-86, and 88 above, and further in view of Scheidt-Puga (WO 2019/038685; Date of Publication: February 28, 2019 – newly cited).
The teachings of Kim and Yang, herein referred to as modified-Kim-Yang, are discussed above as it pertains to purifying rASM.
However, modified-Kim-Yang does not teach: wherein the rASM comprises the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2 (claim 8).
Scheidt-Puga’s general disclosure relates to “using a human acid sphingomyelinase (e.g., olipudase alfa) in treating an abnormal bone condition in acid sphingomyelinase deficiency patients such as low bone density, high bone marrow burden, and other skeletal abnormalities presented in acid sphingomyelinase deficiency patients” (see, e.g., Scheidt-Puga, abstract). Furthermore, Scheidt-Puga teaches administering recombinant human acid sphingomyelinase to patients with abnormal bone conditions (see, e.g., Scheidt-Puga, [0008]).
Regarding claim 8 pertaining to SEQ ID NO: 1, Scheidt-Puga teaches SEQ ID NO: 1, which has 100% sequence identity to instant SEQ ID NO: 1 (see, e.g., Office Action Appendix).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to perform modified-Kim-Yang’s purification methods for a sphingomyelinase, wherein the sphingomyelinase is human olipudase alfa protein, corresponding to SEQ ID NO: 1, as taught by Scheidt-Puga. One would have been motivated to do so because Scheidt-Puga teaches that olipudase alfa is the glycoform alpha of human ASM (EC 3.1.4.12) produced in CHO cells (see, e.g., Scheidt-Puga, [0037]). Moreover, modified-Kim-Yang teaches purification of rhASM produced in CHO cells because rASM derived from CHO cells have superior stability in lyophilized compositions during long term storage (see, e.g., Yang, [0051] & Kim, [0013]). Therefore, based on the teachings of modified-Kim-Yang and Scheidt-Puga, it would have been obvious to purify human olipudase alfa protein, corresponding to instant SEQ ID NO: 1. One would have expected success because modified-Kim-Yang and Scheidt-Puga both teach rhASM compositions.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Kim and Yang as applied to claims 1, 5, 9, 11, 14, 18, 22, 26, 46, 85-86, and 88 above, and further in view of Gruber (U.S. Patent Number 10,259,842; Date of Publication: April 16, 2019 – cited in the IDS filed on 09/24/2025 – previously cited).
The teachings of Kim and Yang, herein referred to as modified-Kim-Yang, are discussed above as it pertains to purifying rASM.
Regarding claim 21 pertaining to the purified rASM preparation, modified-Kim-Yang teaches a composition comprising rASM (see, e.g., Yang, [0036]).
However, modified-Kim-Yang does not teach: wherein the purified rASM preparation has an HCP level not more than 1.0 µg/mg or not more than 5.0 µg/mg
Gruber’s general disclosure relates to “a method for separating a recombinantly produced polypeptide from host cell protein. The method includes a step of loading a clarified cell culture supernatant that includes the recombinantly produced polypeptide and the HCP onto a Protein A chromatography column and washing the Protein A chromatography column with a wash buffer comprising a fatty acid having a chain length of at least about 6 carbon atoms, or a fatty acid salt thereof to remove HCP and then recovering the recombinantly produced polypeptide” (see, e.g., Gruber, abstract). Moreover, Gruber discloses “The presence of HCP can be problematic, not only because of health regulations relating to acceptable levels of contaminants in recombinant antibody products, but also because the presence of HCP can adversely impact product stability and/or efficacy, including, for example, protease activity and formation of visible particulates, fragments or aggregates over time” (see, e.g., Gruber, Section 4.1, pg. 26, col 7, lines 7-13).
Regarding claim 21 pertaining to the HCP level, Gruber teaches HCP levels down to 85 ng/mg when sodium dodecanoate was used in the wash buffer (see, e.g., Gruber, Example 3, pg. 44, col. 43, lines 8-11).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce modified-Kim-Yang’s purified sphingomyelinase preparation, wherein the purified preparation has HCP levels at 85 ng/mg, as taught by Gruber. One would have been motivated to do this because Gruber teaches that “The presence of HCP can be problematic, not only because of health regulations relating to acceptable levels of contaminants in recombinant antibody products, but also because the presence of HCP can adversely impact product stability and/or efficacy, including, for example, protease activity and formation of visible particulates, fragments or aggregates over time” (see, e.g., Gruber, Section 4.1, pg. 26, col 7, lines 7-13). Additionally, Gruber teaches purification of recombinant proteins via various chromatography techniques (see, e.g., Gruber, abstract). Moreover, modified-Kim-Yang teaches methods of purifying sphingomyelinase from bovine brains (see, e.g., Kim, [0035], [0037]) by subjecting the supernatant to hydrophobic interaction chromatography, anion exchange high-performance liquid chromatography, hydrophobic interaction high performance liquid chromatography, and cation exchange fast protein liquid chromatography, in due order (see, e.g., Kim, abstract). Therefore, based on the teachings of modified-Kim-Yang and Gruber, it would have been obvious to produce a purified recombinant protein composition, wherein the recombinant protein composition contains low levels of HCP. One would have expected success because modified-Kim-Yang and Gruber both teach methods of purifying recombinantly-produced proteins.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Kim and Yang as applied to claims 1, 5, 9, 11, 14, 18, 22, 26, 46, 85-86, and 88 above, and further in view of Pan (WO 2008/085988; Date of Publication: July 17, 2008 – cited in the IDS filed on 09/24/2025 – previously cited).
The teachings of Kim and Yang, herein referred to as modified-Kim-Yang, are discussed above as it pertains to purifying rASM.
However, modified-Kim-Yang does not teach: wherein the protein mixture is produced in a bioreactor having a production scale of at least 100L to at least 500L (claim 24).
Pan’s general disclosure relates to “ methods of purifying and analyzing preparations of Fc domain containing polypeptides comprising binding said polypeptide to protein A, more particularly to a protein A column, and eluting with a pH gradient elution system. This method enhances separation of aggregates, multimers and modified versions of the protein from the single Fc domain containing polypeptide” (see, e.g., Pan, abstract). Moreover, Pan discloses the use of CHO host cells because “the efficient DHFR selectable and amplifiable gene expression system allows high level recombinant polypeptide expression in these cells” (see, e.g., Pan, [0040]). Furthermore, Pan discloses the propagation of these cells within bioreactors for production of recombinant proteins (see, e.g., Pan, [0041]-[0042]).
Regarding claim 24 pertaining to production of the protein mixture in a bioreactor, Pan teaches bioreactors for culturing animal cells “in which environmental conditions such as temperature, atmosphere, agitation, and/or pH can be monitored and adjusted” (see, e.g., Pan, [0041]). Moreover, Pan teaches that the bioreactors are used to grow animal cells, such as CHO cells, for the production of recombinant proteins (see, e.g., Pan, [0040]), wherein the bioreactors can contain small scale cultures, such as 100 mL containers, to large scale cultures, such as 15,000 mL containers (see, e.g., Pan, [0042]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce modified-Kim-Yang’s purified sphingomyelinase preparation, wherein the sphingomyelinase preparation is produced in a bioreactor, as taught by Pan. One would have been motivated to do so because Pan teaches that CHO cells can be grown in bioreactors to produce recombinant proteins in a large scale (see, e.g., Pan, [0041]-[0042]). Additionally, Pan teaches that bioreactors for culturing animal cells “in which environmental conditions such as temperature, atmosphere, agitation, and/or pH can be monitored and adjusted” (see, e.g., Pan, [0041]). Moreover, modified-Kim-Yang teaches production of a recombinant human acid sphingomyelinase (rASM) produced in Chinese Hamster Ovary (CHO) cells (see, e.g., Yang, [0036]), and further discloses that composition comprising rASM derived from CHO cells have superior stability in lyophilized compositions during long term storage (see, e.g., Yang, [0051]). Therefore, based on the teachings of modified-Kim-Yang and Pan, it would have been obvious to produce a recombinant sphingomyelinase within a bioreactor. One would have expected success because modified-Kim-Yang and Pan both teach the production of recombinant proteins using CHO cells.
Examiner’s Response to Arguments
Applicant's arguments filed 02/20/2026 have been fully considered but they are not persuasive.
Regarding Applicant’s arguments that Kim does not disclose a recombinant human acid sphingomyelinase (rhASM) (remarks, page 12), this argument is not persuasive because Kim was not relied upon to teach this new limitation. Instead, Yang was relied upon in the 103 rejection above to teach a recombinant human acid sphingomyelinase (see, e.g., Yang, abstract), wherein the rASM is olipudase alfa, which “is the glycoform alpha of a human ASM (EC-3.1.4.12) produced in CHO cells” (see, e.g., Yang, [0036]).
Regarding Applicant’s arguments that Kim’s purification methods cannot be applied to the rhASM taught by Yang because Kim and Yang teach different sphingomyelinase isozymes (remarks, pages 12-13), this argument is not persuasive because Kim teaches chromatography purification methods for sphingomyelinase, such as performing hydrophobic interaction chromatography, anion exchange high-performance liquid chromatography, hydrophobic interaction high performance liquid chromatography, and cation exchange fast protein liquid chromatography, in due order” (see, e.g., Kim, [0013]). Furthermore, Yang teaches recombinant human acid sphingomyelinase (see, e.g., Yang, abstract), wherein the rASM is olipudase alfa, which “is the glycoform alpha of a human ASM (EC-3.1.4.12) produced in CHO cells” (see, e.g., Yang, [0036]). Therefore, both Kim and Yang teach sphingomyelinase; therefore, one of ordinary skill in the art would have been motivated to apply the purification methods taught by Kim to the rhASM taught by Yang because both Kim and Yang teach methods and compositions pertaining to sphingomyelinase. Moreover, Applicant merely provides arguments that the purification methods taught by Kim will not work for the rhASM, as taught by Yang. Applicant provides no actual proof that the purification methods, such as hydrophobic interaction chromatography, anion exchange high-performance liquid chromatography, hydrophobic interaction high performance liquid chromatography, and cation exchange fast protein liquid chromatography, as taught by Kim, will not work for rhASM. MPEP 716.01(c)(II) states “Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984).” Therefore, Applicant’s arguments are not sufficient to overcome the prior arts of record because Applicant has not provided objective evidence.
Regarding Applicant’s arguments pertaining to a POSITA not being motivated to apply the purification methods of Falkenstein to the Kim’s methods of purifying sphingomyelinase (remarks, page 14), this argument is not persuasive because Falkenstein teaches purification of non-glycosylated recombinant proteins (see, e.g., Falkenstein, abstract) by anion exchange chromatography, or cation exchange chromatography, or hydroxylapatite chromatography, or hydrophobic interaction chromatography (see, e.g., Falkenstein, abstract), and Kim teaches purification of sphingomyelinase by hydrophobic interaction chromatography, anion exchange high-performance liquid chromatography, hydrophobic interaction high performance liquid chromatography, and cation exchange fast protein liquid chromatography (see, e.g., Kim, abstract). Therefore, Kim and Falkenstein teach the same method of purifying proteins, which is motivation for one of ordinary skill in the art to apply the methods of Falkenstein to purifying rhASM. Moreover, Falkenstein teaches that hydrophobic charge induction chromatography or anion exchange chromatography can be performed “in flow-through mode with polypeptides having a low or high isoelectric point” to concentrate the polypeptide solution (see, e.g., Falkenstein, pg. 18, col. 10, lines 1-38), which is more motivation for a POSITA to apply the methods of Falkenstein to the methods of Kim and to rhASM, as taught by Yang. Furthermore, the instantly claimed invention does not claim that the rhASM is glycosylated; however, Applicant does not provide any supporting evidence that the methods of Falkenstein cannot be applied to rhASM (see, e.g., MPEP 716.01(c)(II)). Therefore, since Applicant has not provided supportive evidence, just merely arguments, that the methods of Falkenstein cannot be applied to the methods of Kim and the rhASM, as taught by Yang, this argument is not sufficient to overcome the prior arts of record.
Regarding Applicant’s arguments pertaining to unexpected effects (remarks, pages 14-15), this argument is not persuasive because Applicant’s unexpected effects, as demonstrated in Example 1 of the instant specification, are not commensurate in scope with the claimed invention. More specifically, Applicant is relying on different rhASM isoforms (see, e.g., instant specification, Table 1) to show differences in specific activity compared to the monomeric form of rhASM (see, e.g., instant specification, Figure 3). Applicant is relying on different C-terminal modified isoforms to measure specific activity (see, e.g., instant specification, Figure 4). These isoforms are not claimed in the instantly claimed invention; therefore, the results are not commensurate in scope with the instantly claimed invention.
Conclusion
Claims 1-2, 5-6, 8-9, 11-12, 14, 16, 18, 21-22, 24, 26, 46, 85-86, and 88-89 are rejected.
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE IANNUZO whose telephone number is (703)756-5559. The examiner can normally be reached Mon - Fri: 8:30-6:00 EST.
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) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached at (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NATALIE IANNUZO/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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