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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/18/20206 has been entered.
Election/Restrictions
Applicant's election with traverse of Species A (i.e., Single and specific diglycosylated interferon-beta protein indicating single and specific sugar chain structure at positions 25 and 80 of the diglycosylated interferon-beta protein. Applicants’ election: FA2G2S2 at positions 25 and 80) in the reply filed on 12/26/2024 is acknowledged. The traversal is on the grounds that the Office Action has not shown that a serious burden would be required to examine all of the claims, Applicants’ assert examination of all species would not be a burden to the Examiner (see Remarks, filed on 12/26/2024, pg. 1). This is not found persuasive because undue search burden is not a criteria for election/restriction purposes under 35 U.S.C 121 and 35 U.S.C 372.
The requirement is still deemed proper and is therefore made FINAL.
Status of Claims
Claims 1-10 were filed on January 18th 2022.
The amendment filed on July 15th 2025, amended claims 1 and 9-10; and cancelled claims 7-8.
The amendment filed on 02/18/2026, amended claims 1; cancelled claims 5-6; and added new claim 11.
Priority
The present application claims status as a 371 (National Stage) of PCT/KR2020/008847 filed July 7th 2020, and claims priority under 119(a)-(d) to Korean Application No. KR10-2019-0087244 filed on July 18th 2019.
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d) for Korean Application No. KR10-2019-0087244, which papers have been placed of record in the file.
Sequence Interpretation
For claim 2, please note that in light of the transitional phrase “consisting”, the Examiner is interpreting the scope of the interferon-beta protein as closed-ended requiring 100% identity to SEQ ID NO: 1, with any N-/C- terminal additions.
Response to Arguments
1. Applicants’ arguments, see Remarks, filed on 07/15/2025 with respect to the 35 U.S.C. 103 rejection, have been fully considered but are not persuasive. The 35 U.S.C. 103 rejection of claims 1-4 and 9-10 has been maintained.
Response to Amendment
The Declaration of Sunghyun Hong, under 37 CFR 1.132 filed on 02/18/2026 is insufficient to overcome the rejection of claim 1-6 and 9-10 based upon US 2012/0177603 A1, Pub. Date: Jul. 12, 2012 (cited in the IDS filed on 01/18/2018)(herein after “Arnold et al.”); in view of US 2013/0302281 A1 Pub. Date: Nov. 14, 2013 (herein after “DiBiase et al.”); and Song et al., PLOS One, May 2014, vol. 9, issue 5, pp. 1-14 (cited in the IDS filed on 01/18/2022)(herein after “Song et al.”), as evidenced by Sigma-Aldrich., Product Information – CM Sepharose®, revised 01/2022, pp. 1-2, available online at https://www.sigmaaldrich.com/deepweb/assets/sigmaaldrich/product/documents/131/832/ccf100pis-ms.pdf, accessed on 04/14/2025 (herein after “ Sigma-Aldrich 1”); in further view of Betts et al., Chapter 14 -Amino Acid Properties and Consequences of Substitutions in Bioinformatics for Geneticists, Edited by Michael R. Barnes and Ian C. Gray, 2003, pp. 297-316 (herein after “Betts et al.”), as evidenced by GenCore, Sequence Alignment, Song’s sequence in Figure_S1 vs Instant SEQ ID NO: 1 (herein after “GenCore”); as set forth in the last Office action for the following reasons:
Declarant’s assertion of evidence of unexpected results in the prosecution of U.S. Patent Application No. 17/627,840 is found unpersuasive. The Declarant argues that they have surprisingly and unexpectedly found a superior effect of using butyl Sepharose resin for the hydrophobic interaction chromatography in step (d) of claim 1 and a superior effect of using Q resin for hydrophobic anion-exchange chromatography in step (e) of claim 1.
Pursuant to MPEP 716.02(e), an affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). "A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference." In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960) (deviations from example were inconsequential).
In the instant case, Applicant/Declarant (i.e., Sunghyun Hong) fails to explain, note or evaluate the significance of the results displayed in Table 1 and Figs. 1A-1C for the purification of diglycosylated interferon beta protein obtained with HIC and AEX, in relation the purification method taught by Arnold et al. in US 2012/0177603 A1.
Since a comparison between Declarant’s unexpected and significantly superior results have not been compared to the cited prior art. Declarant’s assertions that “the use of butyl Sepharose resin in an optimized HIC process provides an unexpected and significantly superior effect in purifying the diglycosylated interferon protein” and that “Q resin as used for AEX provides unexpected and significantly superior effects in purifying the diglycosylated interferon beta protein compared to other anion exchange resins” are mere conclusions and thus not entitled to the weight of conclusions accompanying the evidence provided in the declaration.
Moreover, pursuant to MPEP 716.02(d), whether the unexpected results are the results of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” The unexpected and superior results reported by the Declarant are not commensurate in scope with the instant claims, because it is not readily apparent whether the data depicted in Table 1 and Figs. 1A-1C was obtained by following the same steps as recited in instant claim 1. This uncertainty is due to the fact that it is not readily apparent whether the same parameters were applied when testing the different resins. Therefore, without further clarification of the critical parameters such as pH, buffer, type of salt, salt concentration, buffer type and temperature, a determination of whether the scope of instant claim 1 is commensurate in scope with the unexpected results cannot be made. Therefore, Declarant’s argument of surprising and unexpected results is not persuasive.
Maintained/Modified Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness
(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
1. Claims 1-4 and 9-11 are rejected under 35 U.S.C. 103 as being unpatentable over of US 2012/0177603 A1, Pub. Date: Jul. 12, 2012 (cited in the IDS filed on 01/18/2018)(herein after “Arnold et al.”), as evidenced by Yang et al. Anal. Chem. 2018, 90, 14294-14302 (herein after “Yang”); in view of US 2013/0302281 A1 Pub. Date: Nov. 14, 2013 (herein after “DiBiase et al.”); Mitsubishi Chemical Group., Strongly Basic Anion Exchange Resins DIAIONTM series, pp. 1-3, first available online on 07/15/2019, retrieved from https://www.m-chemical.co.jp/en/products/departments/mcc/ion/product/1201066_8072.html, on 05/28/2026 (herein after “MCG”), Song et al., PLOS One, May 2014, vol. 9, issue 5, pp. 1-14 (cited in the IDS filed on 01/18/2022)(herein after “Song et al.”) as evidenced by GenCore, Sequence Alignment, Song’s sequence in Figure_S1 vs Instant SEQ ID NO: 1 (herein after “GenCore”), and Betts et al., Chapter 14 -Amino Acid Properties and Consequences of Substitutions in Bioinformatics for Geneticists, Edited by Michael R. Barnes and Ian C. Gray, 2003, pp. 297-316 (herein after “Betts et al.”).
Regarding claim 1, Arnold et al. teach a method for the production of human glycosylated Interferon-beta (INF-ß), comprising two affinity chromatography steps followed by hydrophobic interaction chromatography step preferably with a subsequent anion exchange chromatography step (see Abstract). Thereby constituting a method for purifying INF-ß protein. Arnold et al. add that cell culture supernatant or cell fractions containing IFN-ß serve as starting material for the chromatographic purification (see, pg. 2, para[0025]), and that glycosylated INF-ß, preferably recombinant INF-ß from eukaryotic host cells, preferably CHO cells is used (see pg. 2, para[0025]).
As evidenced by Yang et al., CHO cell line major expression system used for the efficient production of recombinant proteins, the majority of which are therapeutic glycoproteins (see pg. 14294, left column, 1st para). Yang et al. revealed the macro-heterogeneity and micro-heterogeneity of glycoproteins in CHO cell lysate and medium (see pg. 14298, left column, last para). From the 530 N-linked glycoproteins identified from the intact glycoproteomic analysis, approximately 51.9% of the glycoproteins were identified with one N-linked glycosite, 24.2% of them were detected with two N-linked glycosites, and 10.4% with three N-linked glycosites (see pg. 14298, right column, 1st para). A total of 55 (8.7%) glycoproteins that contained at least five glycosites were also identified (see pg. 14298, right column, 1st para). However, the average number of N-linked glycosites was 2.2 per glycoprotein (see pg. 14298, right column, 1st para). As such, the teachings of Arnold et al. as evidenced by Yang et al. are suggestive of a culture solution comprising a diglycosylated interferon-beta expressed in a host cell, thereby corresponding to instant step (a).
Arnold et al.’s method comprises at least one affinity chromatography (AC) step, and at least one at least one hydrophobic interaction chromatography (HIC) step, wherein the affinity chromatography step(s) and the hydrophobic interaction chromatography step(s) are applied immediately succeeding one another in either order (see pg. 10, claim 1). Thereby constituting wherein affinity chromatography is performed for the culture solution, as recited in instant step (b) and also constituting wherein HIC is performed for the solution obtained in step c, as recited in instant step (d).
Arnold et al. add that the feasibility of using hydrophobic interaction chromatography on Butyl Sepharose FF is demonstrated yielding in approximately 60% after optimization of buffer system and temperature; and therefore, hydrophobic interaction chromatography, using butyl Sepharose resin (GE Healthcare), is performed (see pg. 8, para[0086]), thereby constituting wherein butyl Sepharose as a resin is used, as recited in instant step (d). Similarly, Arnold et al. teach that that for the anion exchange membrane filtration step, a membrane with quaternary amino groups is used (see pg. 4, para[0049] and pg. 10, claim 6).
Arnold et al. also teach that for removal of possible existing remaining host cell DNA and potential viral contamination and other negatively charged contamination, the purification method for IFN-ß comprises an anion exchange chromatography (AEX) step, preferably directly applied after the HIC step in flow through modus (see pg. 2, para[0031]). Arnold et al. also teach that the Cation Exchange Chromatography (CEX) step might be more suitable as a polishing step (see pg. 3, para[0032]), thereby constituting wherein cation-exchange chromatography is performed for the solution obtained in step (e), as recited in instant step (f).
However, Arnold et al. do not expressly teach a method for purifying a diglycosylated INF-ß protein comprising step (c) low pH inactivating the solution obtained in step (b), wherein the low pH is pH 4.0 or less, nor performing anion-exchange chromatography for the solution obtained in step (d) using a Q resin as a resin.
DiBiase et al. teach that human interferon-beta can be stabilized when placed in buffered solutions having a pH between about 4 and 7.2 (see pg. 1, para[0007]). DiBiase et al. also teach that the purified interferon is acidified and held at low pH to inactivate any remaining viruses (see pg. 4, para[0049]); thereby constituting wherein the method comprises low pH inactivating the solution obtained in step b, wherein the low pH is 4.0 or less as recited in instant claim 1, step (c).
Similarly, Arnold et al. teach that early inactivation of potentially present enzymes or viruses can be achieved in the HIC by elution with organic solvents (see pg. 4, para[0047]).
As such, the inactivation step is clearly a result specific parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine when (i.e., order of steps) in the purification method to perform inactivation of the solution with low pH in order to achieve the desired results. Thus, an ordinary skilled artisan would have been motivated to modify the purification method taught by Arnold et al., by acidifying the purified interferon, because an ordinary skilled artisan would have been able to utilize the teachings of DiBiase et al. to lower the pH to 4.0 or less and obtain a stable and purified interferon-beta with a reasonable expectation of success. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of the inactivation step (i.e., step c) in a method for purifying a diglycosylated interferon-beta protein would have been obvious before the effective filing date of Applicant's invention. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at before the effective filing date of the claimed invention, because the combined teachings of the prior art are fairly suggestive of the claimed method as recited in instant claim 1.
As such, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Arnold with the teachings of DiBiase in order to arrive at the claimed method for purifying a diglycosylated IFN-ß comprising low pH inactivation wherein the low pH is pH 4 or less. One of ordinary skill in the art would have been motivated to do so because it was known that IFN-ß can be stabilized when placed in buffered solutions having a pH between about 4 and 7.2, and also because it was known that purified interferon is acidified and held at low pH to inactivate any remaining viruses, as taught by DiBiase. One of ordinary skill in the art would have had a reasonable expectation of success given that early inactivation of potentially present enzymes or viruses can be achieved in the HIC by elution with organic solvents as taught by Arnold. Therefore, incorporating a low pH inactivating step as part of the purification process would support the instantly claimed method by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, and/or the combination of prior art elements according to known methods to yield predictable results, pursuant to KSR.
With respect to using a Q resin as a resin, as recited in step (e); as previously mentioned, Arnold et al. teach using a membrane with quaternary amino groups for the anion exchange membrane filtration (see pg. 4, para[0049]) and pg. 10, claim 6).
MCG teaches that the strongly basic anion exchange resin is an anion exchange resin with quaternary ammonium groups incorporated into the styrene frame (see pg. 1, characteristics). Applications include water treatment as well as purification of pharmaceuticals and food and the usage encompasses packed column or batch processing (see pg. 1, Applications).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Arnold by substituting the membrane with quaternary amino groups in the anion exchange membrane filtration step, with strongly basic anion exchange resin of MCG in order to arrive at the claimed method for purifying a diglycosylated IFN-ß. One of ordinary skill in the art would have been motivated to do so because it was known that anion exchange resins with quaternary ammonium groups incorporated into the styrene frame are used in the purification of pharmaceuticals and in packed column or batch processing, as taught by MCG. One of ordinary skill in the art would have had a reasonable expectation of success given that a membrane with quaternary amino groups was used as part of the method of Arnold. Therefore, substituting Arnolds membrane with a strong anion exchange resin with quaternary ammonium groups incorporated into the styrene frame would support the instantly claimed method by constituting a simple substitution of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Regarding claim 2, Arnold et al. teach that IFN-ß intended for purification is a polypeptide which exhibits biological and/or immunological features of naturally occurring human IFN-ß and can be either a natural or a recombinant IFN-ß (see pg. 2, para[0025]).
However, Arnold et al. do not expressly teach wherein the interferon-beta protein consists of a peptide sequence of SEQ ID NO: 1, as recited in instant claim 2.
Song et al. teach gene construction, expression and purification of rhIFN-ß 1a glycosylation analogs (see pg. 2, left column). Glycosylation analogs were constructed by performing site direct mutagenesis on wild-type human IFN-ß (see pg. 2, left column, paragraph 5). Hyperglycosylation via site-directed mutagenesis resulted in the development of a new molecular entity termed R27T (see pg. 2, left column, paragraph 3), with two N-glycosylation sites at the 80th (original site) residue and at the 25th residue (i.e., additional site) (see pg. 1, Abstract). Purification of rhIFN-ß 1a and rhIFN-ß mutain proteins (i.e., R27T) was performed by applying the culture fluid containing proteins to a column of blue Sepharose 6FF; which was then eluted with 35% propylene glycol-based phosphate buffer. After elution, the eluate was sequentially loaded onto CM Sepharose FF and to C4 Reverse phase-high performance liquid chromatography (RP-HPLC) (see pg. 2, left column, paragraph 5). Song et al., also performed biophysical analysis of protein stability by DSC of rhIFN-ß 1a and R27T (diglycosylated IFN-ß) in 20 mM acetate buffer pH 4.2 (see pg. 6, right column, second to last paragraph). Song et al., also teach that glycoengineering had no effect on rhIFN-ß ligand-receptor binding, as no loss of specific activity was observed; and that the rhIFN-ß mutain proteins (i.e., R27T) with two N-glycosylation sites at the 80th (original site) residue and at the 25th residue had improved stability and reduced propensity for aggregation as well as increased half-life ( see pg. 1, Abstract).
Song et al. teach that to maintain the structural and functional properties of the protein, additional N-glycosylations sites were not created in the five helical regions, consisting of amino acid residues A(2-22), B(51-71), C(80-107), D112-136) and E(139-162) (see pg. 6, left column, paragraph 1). Song et al. also teach Figure S1 which depicts an amino acid sequence which is 166 residues in length (see Supplemental Information, Figure S1 A & B). Upon comparing instant SEQ ID NO: 1 with the sequence depicted in Figure S1 B, the percent identity between both sequences is 99.0 % (see GenCore, pg. 1). The one percent difference is due to the presence of three conservative substitutions from residues 75-77, where alanine is present as a tripeptide (i.e., AAA) in Song’s sequence, while a serine tripeptide (i.e., SSS) is present in instant SEQ ID NO: 1 (see GenCore, pg. 1).
Betts et al., teach the amino acids alanine, cysteine, glycine, proline, serine and threonine are often grouped together for the simple reason that they are all small in size; and in some protein structural context, substitution of a small side chain for a large one can be disastrous (see pg. 299, section 14.4.3). Betts et al. also teach that alanine can be substituted by other small amino acids and that alanine is probably the dullest amino acid for this reason it is not surprising to see alanine present in just about all non-critical protein contexts (see pg. 300, section 14.5.1.2). Additionally, Betts et al. mention that serine can be substituted by other polar or small amino acids and being a fairly indifferent amino acid, serine can reside both within the interior of a protein, or on the protein surface (see pg. 307, sections 14.5.16.1 and 14.5.16.2).
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the INF-ß sequence taught by Song et al. as part of a method for the production of human glycosylated INF-ß of Arnold et al. in order to arrive at the claimed INF-ß protein consisting of a peptide sequence of SEQ ID NO: 1. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because Song’s INF-ß sequence is 99.0% identical to instant SEQ ID NO: 1, because the 1% differences between both sequences is due to the presence of the tripeptide A-A-A at residues 75-76-75 in Song’s INF-ß sequence. One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that Song’s sequence does not include N-glycosylations at residues 75-77; given that, the amino acid serine is small in size and in some protein structural context, substitution of a small side chain for a large one can be disastrous; and given that serine can be substituted by other polar or small amino acids (i.e., alanine), and since alanine is probably the dullest amino acid for this reason it is not surprising to see alanine present in just about all non-critical protein contexts, as taught by Betts et al. Therefore, incorporating the INF-ß sequence taught by Song et al. as part of a method of the production of human glycosylated Interferon-beta (INF-ß) of Arnold et al. would support a method for purifying a diglycosylated interferon-beta protein, wherein the INF-ß protein consists of a peptide sequence of SEQ ID NO: 1, by constituting the simple substitution of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Regarding claim 3, Arnold et al. teach that that cell culture supernatant or cell fractions containing IFN-ß serve as starting material for the chromatographic purification (see, pg. 2, para[0025]), and that glycosylated INF-ß, preferably recombinant INF-ß from eukaryotic host cells, preferably CHO cells is used (see pg. 2, para[0025]).
Regarding claim 4, Arnold et al. teach that the harvest (H) derived from 7 day collection (i.e. Hl to H4) is first captured by affinity chromatography, using Blue Sepharose FF resin (GE Healthcare) (see pg. 7, para[0082]).
Regarding claim 9, Song et al. teach glycosylation analogs of wild-type human IFN-ß (see pg. 2, left column, paragraph 5), where hyperglycosylation via site-directed mutagenesis resulted in the development of a mutant with two N-glycosylation sites at the 80th (original site) residue and at the 25th residue (i.e., additional site) (see pg. 1, Abstract), thereby constituting wherein the interferon-beta protein has sugar chains at amino acid positions 25 and 80 as recited in instant claim 9.
Regarding claim 10, Song et al. teach that for modeling N-glycosylation, one of the major oligosaccharide structures (FA2G2S2, F: Core fucosylated, A2: Biantennary with both GlcNAcs as b1-2 linked, G2: two galactoside linked beta 1-4 to antenna, S2: two sialic acids linked to galactose) was chosen using a structure obtained from the hydrophilic interaction liquid chromatography (HILIC) profiles of R27T (see pg. 3, right column, paragraph 2). Thereby constituting wherein the interferon-beta protein includes any two sugar chain structures of FA2G2S2 as recited in instant claim 10.
Regarding claim 11, as previously mentioned, MCG teaches that the strongly basic anion exchange resin is an anion exchange resin with quaternary ammonium groups incorporated into the styrene frame (see pg. 1, characteristics), thereby corresponding to wherein the anion-exchange chromatography is performed using a strong quaternary ammonium (Q) anion exchanger resin.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Response to Arguments
Applicants assert that in light of the unexpected and superior results of the currently claimed method of purifying a diglycosylated interferon beta protein, the currently amened claim 1 is not obvious over the cited prior art (see remarks, filed 02/18/2026, pg. 6 of 6, 2nd full paragraph). These arguments have been fully considered but are not persuasive.
As discussed in the “Response to Amendment” section above, the Declarant’s arguments are not persuasive because a comparison of the evidence provided (i.e., Table 1 and Figs. 1A-1C) and the closest prior is missing. As such, the assertions pertaining to the unexpected and significant superior effect in purifying the diglycosylated interferon beta protein with butyl Sepharose resin and with a Q resin, are mere conclusions and thus do not overcome the 35 U.S.C 103 rejection of claims 1-4 and 9-11.
Furthermore, even if the unexpected results were evidence of unobviousness; pursuant under MPEP 716.02(d), whether the unexpected results are the results of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.”
With respect to claim 1, the scope of the claimed method comprises hydrophobic interaction chromatography, anion-exchange chromatography and cation exchange chromatography. Thus, the scope of claim 1 encompasses different operational parameters for the purification of the diglycosylated interferon protein. Upon reviewing the evidence provided by the Declarant, it is not readily apparent whether the unexpected results where obtained under the same operational parameters. Therefore, the unexpected results are not commensurate in scope with the instant claims.
Accordingly, claims 1-4 and 9-11 stand rejected under 35 U.S.C. 103.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CLAUDIA E ESPINOSA whose telephone number is (703)756-4550. The examiner can normally be reached Monday-Friday 9:30-5:30 EST.
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/CLAUDIA ESPINOSA/Patent Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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