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 .
Information Disclosure Statement
The listing of references in the PCT international search report is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, “the list ... must be submitted on a separate paper.” Therefore, the references cited in the international search report have not been considered. Applicant is advised that the date of submission of any item of information in the international search report will be the date of submission of the IDS for purposes of determining compliance with the requirements for the IDS with 37 CFR 1.97, including all timing statement requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Claim Objections
Claims 1, 2, and 4-11 are objected to because of the following informalities:
a) in claim 1, line 2, “presents” should be – present --;
b) claim 1, line 2, “comprising;” should be – comprising: --[colon];
c) in claim, 1, step (d), “in” should be – into a --;
d) in claim, 1, step (e), “in” should be – into --;
e) in claim 1, step (f), “wherein the treated protein mixture comprises protein to SDS ratio is higher than 2.7:1…” should be -- wherein the treated protein mixture comprises the protein to SDS ratio being higher than 2.7:1;
f) in claim 2, line 1, the indefinite article – a - should be inserted between “is” and “fusion”;
g) in claim 4, line 1, -- (LMW) – should be inserted between “weight”
and ”impurities”;
h) in claim 4, line 2, the indefinite article – a – should be inserted between “a)” and “first”;
i) in claim 4, line 3, “comprises;” should be replaced with – comprising: --;
j) in claim 4, line 6, “third and fourth” should be replaced with – a third and a fourth --;
k) in claim 5, line 1, the definite article – the – should be inserted between “comprises” and “protein”;
l) in claim 6, line 1, the definite article – the – should be inserted between “in” and “treated”;
m) in claim 7, line 2, “impurity” should be – impurities --;
n) in claim 8, line 2, “impurity” should be – impurities --;
o) in claim 9, line 2, “impurity” should be – impurities --;
p) in claim 10, line 1,the definite article – the – should be inserted between “of” and “low”;
q) in claim 11, line 1, the indefinite article – a – should be inserted between “at” and “suitable”; and
r) in claim 11, line 2, “protein” should be – proteins –.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Note that dependent claims will have the deficiencies of base and intervening claims.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention:
a) the claim 1 preamble is, “An improved process for the separation of more than two low molecular weight proteins . . . . [italicizing by the Examiner]”. The scope of the phrase “low molecular weight proteins ” is vague. Although Applicant has a definition of “low molecular weight” in his specification1 this definition defines the phrase relative to “fusion protein” and “product-related impurities”, which are nowhere in the claim. So, it is not clear how Applicant’s definition of “low molecular weight” limits the scope of the phrase “low molecular weight proteins ” in claim 1.
b) claim 1 recites the limitation "the protein mixture" in line 2. There is insufficient antecedent basis for this limitation in the claim;
c) claim 1 reads in part as follows
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There should be a verb, such as “providing a”, between “a)” and “protein”, as “a)” is understood to be a process step.
d) claim 1 recites the limitation "the impurity" in line 3. There is insufficient antecedent basis for this limitation in the claim;
e) claim 1 recites the limitation "the protein of interest" in line 3. There is insufficient antecedent basis for this limitation in the claim;
f) claim 1, step (b), recites, “with sodium dodecyl sulphate or SDS [italicizing by the Examiner]”, but does not “SDS” stand for “sodium dodecyl sulphate” as Applicant’s specification, page 7, line 17, states, ‘The term "SDS" refers to Sodium dodecyl sulfate.’?
g) claim 1 recites the limitation "treated protein" in line 7. There is insufficient antecedent basis for this limitation in the claim;
h) claim 1, step e, requires “performing CE-SDS by injecting the treated protein mixture in a CE-instrument; . . . . [italicizing by the Examiner]” However, the immediately preceding step (d) is “injecting the treated protein mixture in CE-instrument; . . .” See step (e) is redundant with step (d);
i) claim 1, step e, requires “performing CE-SDS by injecting the treated protein mixture in a CE-instrument; . . . . [italicizing by the Examiner]” However, one of ordinary skill in the art would take injecting a sample into a CE instrument as performing CE (capillary electrophoresis), but a preliminary step to performing CE or an initial step to performing CE. Is Applicant indicating that nothing more needs to be done in order to perform CE on the treated protein mixture than injecting the treated protein mixture in a CE-instrument?
j) claim 1, step (f), requires “wherein the treated protein mixture comprises protein to SDS ratio is higher than 2.7:1.” Is this ratio a molar ratio?
k) claim 1, step (f), requires “wherein the treated protein mixture comprises protein to SDS ratio is higher than 2.7:1.” Is this a ratio of total protein to SDS?
l) claim 1, step (f), requires “wherein the treated protein mixture comprises protein to SDS ratio is higher than 2.7:1.” It is not clear how the word “comprises” is meant to affect the stated ratio. Does Applicant mean -- wherein in the treated protein mixture the ratio of protein to SDS
m) in claim 4, step (b)(i), the scope of the phrase “first LMW about 80 kda;” is not clear. Does Applicant mean – a first LMW having MW about 80 kda --?
n) in claim 4, step (b)(iii), the scope of the phrase “second LMW about 45 kda;” is not clear. Does Applicant mean – a second LMW having MW about 45 kda --?
o) in claim 4, step (b)(iii) the scope of the phrase “third and fourth LMW about 25 kda to 30 kda” is not clear. Does Applicant mean – a third and a fourth LMW each with a MW within about 25 kda to about 30 kda?
o) in claim 6 the scope of the phrase “the protein concentration in treated protein mixture” is indefinite. Is this protein concentration the total protein concentration, the concentration of just the protein of interest?
p) claim 7 recites the limitation " more than two low molecular weight impurity " in lines 1-2 . There is insufficient antecedent basis for this limitation in the claim.
q) in claim 7 the additional limitation of this claim, “. . . ., wherein the separation or quantification of more than two low molecular weight impurity is improved compared to CE-SDS performed at protein concentration below 2.7 mg/ml…”, is completely unclear as it is not clear what separation or quantification is being compared to CE-SDS performed at protein concentration below 2.7 mg/ml. Additionally, the operational conditions of the separation or quantification of more than two low molecular weight impurity and of the CE-SDS performed at protein concentration below 2.7 mg/ml are completely unspecified.
r) in claim 8 the additional limitation of this claim, “. . . ., wherein the separation or quantification of more than two low molecular weight impurity is improved compared to CE-SDS performed at protein concentration below 3.6 mg/ml…”,
is completely unclear as it is not clear what separation or quantification is being compared to CE-SDS performed at protein concentration below 3.6 mg/ml. Additionally, the operational conditions of the separation or quantification of more than two low molecular weight impurity and of the CE-SDS performed at protein concentration below 3.6 mg/ml are completely unspecified.
s) in claim 9 the additional limitation of this claim, “. . . ., wherein the separation or quantification of more than two low molecular weight impurity is improved compared to CE-SDS performed at protein concentration below 4.5 mg/ml…”,
is completely unclear as it is not clear what separation or quantification is being compared to CE-SDS performed at protein concentration below 4.5 mg/ml. Additionally, the operational conditions of the separation or quantification of more than two low molecular weight impurity and of the CE-SDS performed at protein concentration below 4.5 mg/ml are completely unspecified.
t) in claim 10 how, if at all, is the “low molecular weight impurity” related to the “more than two low molecular weight proteins” or the “ at least the impurity” in underlying claim 1?
u) in claim 12 the scope of the phrase “post final purification steps” is indefinite as the purification process is not specified.
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.
Claims 1, 2, and 5-12 are rejected under 35 U.S.C. 103 as being obvious over Roshan Upadhyay WO 2021/009669 A2 (hereafter “Upadhyay”) in view of in view of Shen et al., “Formation of an Unprecedented Impurity during CE-SDS Analysis of a Recombinant Protein,” Pharm. Res. (2020) 37:228 (hereafter “Shen”) or Ares Trading S.A. EP 3620785 A1 (hereafter “Ares”).
The applied reference has a common inventor and assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
Addressing claim 1, as a first matter the scope of the phrase “low molecular weight proteins ” is vague. Although Applicant has a definition of “low molecular weight” in his specification2 this definition defines the phrase relative to “fusion protein” and “product-related impurities”, which are nowhere in the claim. So, it is not clear how Applicant’s definition of “low molecular weight” limits the scope of the phrase “low molecular weight proteins ” in claim 1. In any event, Upadhyay does use the phrase “low molecular weight”, which is defined on page 6, line 26 – page 7, line 6.
Upadhyay discloses an improved process for the separation of more than two low molecular weight proteins present in a protein mixture (see the Abstract, page 1,
lines 1-7; page 15, lines 5-6 (“In certain embodiments, the protein mixture comprises a plurality of proteins and protein of interest. [italicizing by the Examiner]“); and page 15, lines 22-24 (“In certain embodiments, the treated protein mixture comprises an aqueous or buffer solution containing a protein mixture optionally having at least one LMW impurity, a protein of interest, SDS, and B-mercaptoethanol.“) comprising:
a) providing a protein mixture comprising at least an impurity and the protein of interest (page 1, lines 1-7; and page 15, lines 22-24), wherein the protein mixture does not contain a full-length antibody having molecular weight about 150 kda (page 15,
lines 3-5; and page 17, lines 8-10);
b) mixing the protein mixture at a suitable ratio with sodium dodecyl sulphate or SDS to treated protein mixture (page 15, lines 17-18; page 15, lines 22-24; and claim 1, step (b); and claim 4);
c) optionally incorporating a 10 kDa marker into the treated protein mixture (although this step is optional and so does not necessarily need to be met, it is actually disclosed by Upadhyay. See page 19, line 15; and claim 1, step (c));
d) injecting the treated protein mixture in CE-instrument (page 8, line 31; and claim 1, step (d));
e) performing CE-SDS by injecting the treated protein mixture in a CE-instrument (page 9, lines 1-2; and claim 1, step (e)).
Upadhyay, though, does not disclose performing the step of “f) separating more than two low molecular weight proteins; wherein the treated protein mixture comprises protein to SDS ratio is higher than 2.7:1.” As for “separating more than two low molecular weight proteins”, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to do so because although in the working examples there is only one impurity (LMW species) to separate from the target protein (see, for example, Figure 1 and page 19, line 25 – page 20, line 3), as indicated above Upadhyay does disclose that more than one LMW impurity may be present in the sample mixture and the purpose of the invention of Upadhyay is
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See Upadhyay page 1, lines 3-7.
As for the claim 1 limitation “. . . .; wherein the treated protein mixture comprises protein to SDS ratio is higher than 2.7:1…”, Shen discloses performing capillary electrophoresis on fusion proteins using sodium dodecyl sulfate (SDS). Moreover, Shen discloses that SDS may be a result effective variable affecting peak resolution depending on what additives may be present in capillary electrophoresis electrolyte buffer. See Shen the Abstract, Effects of SDS on the Formation of the Shoulder Peak Impurity with or without IAM, which is on page 5 of 12, and Figures 4 and 5. Ares discloses performing capillary gel electrophoresis on fusion proteins using SDS within a range of 1 to 10%3. See Ares the title, Abstract, paragraphs [0001] and [0005], and claim 6. In light of Shen, to have the treated protein mixture comprise protein to SDS ratio be higher than 2.7:1 is prima facie obvious as routine optimization of CE peak resolution corresponding to one or more proteins of interest. See MPEP 2144.05(II). Alternatively, in light of Ares, to have the treated protein mixture comprise protein to SDS ratio be higher than 2.7:1 is, barring evident to the contrary, such as unexpected results, prima facie obvious as an arbitrary choice.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Addressing claim 2, for the additional limitation of this claim see Upadhyay
page 5, line 28 – page 6, line 1; and page 14, lines 22-23. Also, recall from the rejection of underlying claim 1 that both Shen and Ares also disclose having the protein of interest be a fusion protein.
Addressing claim 5, for the additional limitation of this claim although Upadhyay as modified by Shen or Areas does not specifically disclose “. . . .wherein the treated protein mixture comprises protein to SDS ratio selected from about 3:1, about 3.6:1, about 4.5, and about 5:1…”, in the same manner as discussed in the rejection of underlying claim 1 regarding eh limitation “. . . .; wherein the treated protein mixture comprises protein to SDS ratio is higher than 2.7:1…” to have the protein to SDS ratio be one of those listed in claim 5 is either prima facie obvious routine optimization of a known result effective variable (in order to optimized CE peak resolution of the protein of interest – Shen) or an arbitrary choice (Ares).
Addressing claim 6, as a first matter the scope of the phrase “the protein concentration in treated protein mixture” is indefinite. See the rejection of this claim 6 under 35 U.S.C 112(b) above. In any event rend3ers the additional limitation of this obvious, if not anticipates it, as Upadhyay discloses, on page 15, lines 14-16, “In an embodiment the protein mixture is at least about 2mg/ml. In certain embodiment the protein mixture is selected from about 2mg/ml, about 3 mg/ml, about 4mg/ml, about 5mg/ml. In an embodiment the protein mixture is at least about 5mg/ml. [italicizing by the Examiner]” See MPEP 2144.05(I).
Addressing claim 7, as a first matter the additional limitation of this claim, “. . . ., wherein the separation or quantification of more than two low molecular weight impurity is improved compared to CE-SDS performed at protein concentration below 2.7 mg/ml…”, is completely unclear as it is not clear what separation or quantification is being compared to CE-SDS performed at protein concentration below 2.7 mg/ml. Additionally, the operational conditions of the separation or quantification of more than two low molecular weight impurity and of the CE-SDS performed at protein concentration below 2.7 mg/ml are completely unspecified. Thus, it is not clear how claim 7 further limits the process of underlying claim 1. Since Upadhyay discloses, on page 12, lines 3-4, “f. Detecting and quantifying the LMW impurity wherein quantification and/or detection of LMW impurity is improved compared to CE-SDS performed at 25°C….”, the Examiner, as he best understands claim 7, assumes that the additional limitation of claim 7 is inherently met by Upadhyay as modified by Shen or Ares.
Addressing claim 8, as a first matter the additional limitation of this claim, “. . . ., wherein the separation or quantification of more than two low molecular weight impurity is improved compared to CE-SDS performed at protein concentration below 3.6 mg/ml…”, is completely unclear as it is not clear what separation or quantification is being compared to CE-SDS performed at protein concentration below 3.6 mg/ml. Additionally, the operational conditions of the separation or quantification of more than two low molecular weight impurity and of the CE-SDS performed at protein concentration below 3.6 mg/ml are completely unspecified. Thus, it is not clear how claim 8 further limits the process of underlying claim 1. Since Upadhyay discloses, on page 12, lines 3-4, “f. Detecting and quantifying the LMW impurity wherein quantification and/or detection of LMW impurity is improved compared to CE-SDS performed at 25°C….”, the Examiner, as he best understands claim 8, assumes that the additional limitation of claim 8 is inherently met by Upadhyay as modified by Shen or Ares.
Addressing claim 9, as a first matter the additional limitation of this claim, “. . . ., wherein the separation or quantification of more than two low molecular weight impurity is improved compared to CE-SDS performed at protein concentration below 4.5 mg/ml…”, is completely unclear as it is not clear what separation or quantification is being compared to CE-SDS performed at protein concentration below 4.5 mg/ml. Additionally, the operational conditions of the separation or quantification of more than two low molecular weight impurity and of the CE-SDS performed at protein concentration below 4.5 mg/ml are completely unspecified. Thus, it is not clear how claim 9 further limits the process of underlying claim 1. Since Upadhyay discloses, on page 12, lines 3-4, “f. Detecting and quantifying the LMW impurity wherein quantification and/or detection of LMW impurity is improved compared to CE-SDS performed at 25°C….”, the Examiner, as he best understands claim 9, assumes that the additional limitation of claim 9 is inherently met by Upadhyay as modified by Shen or Ares.
Addressing claim 10, for the additional limitation of this claim see Upadhyay
page 12, lines 1-4, and page 12, lines 13-16.
Addressing claim 11, although Upadhyay discloses performing the CE separation for at least 30 minutes (see claim 14), Upadhyay does also clearly disclose that the migration times of the sample proteins decreases with increasing temperature. See Figure 1 and page 5, lines 6-8. Also, one of ordinary skill in the capillary electrophoresis art would expect that increasing the CE separation voltage will decease that the migration times of the sample proteins. So, to perform in the process of Upadhyay as modified by Shen or Ares the CE-SDS at a suitable separation voltage to separate four low molecular weight protein in less than 22 minutes is just a matter of increasing the voltage above what is disclosed by Upadhyay (for example, see page 5, lines 1-2) and/or increasing the capillary temperature. The extent to which migration time can be reduced from, say, 30 minutes to the claimed less than 22 minutes is only limited by the acceptable loss of peak resolution of for the proteins of interest, for example, if their presence in the sample only needs to be deteioemed, not quantitation, then loss of peak resolution is more acceptable.
Addressing claim 12, as a first matter the additional limitation of this claim is being interpreted as a product-by-process limitation. As such the claim is not limited to the manipulation of the recited step, only the structure (here actually composition) implied by the step. See MPEP 2113. Moreover, it is not clear how whether the protein mixture is obtained by harvest or post affinity chromatography or post final purification steps would necessarily differentiate the claimed protein mixture from that used in the process of Upadhyay as modified by Shen or Ares, especially when there is no indication by Applicant as to what the starting material for the creating the protein mixture is and what the operational conditions for the harvest or post affinity chromatography or post final purification steps are. Thus, claim 11 maybe rejected on the same basis upon which underlying claim 1 has been rejected.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Upadhyay in view of Shen or Ares as applied to claims 1, 2, and 5-12 above, and further in view of Gray et al. US 2002/0114814 A1 (hereafter ‘Gray”).
Addressing claim 3, while Upadhyay as modified by Shen or Ares does not disclose “. . . ., wherein the fusion protein is CTLA4-IgG having molecular weight less than 100 kda…”, Upadhyay does disclose that the fusion protein may comprise an antibody (see page 14, lines 22-24), that is, Upadhyay the “genus” for species CTLA4-IgG having molecular weight less than 100 kda.
Gray discloses CTLA4-immunoglobulin fusion proteins, such as CTLA4-IgG1 fusion protein. See that Abstract. paragraph [0006], and claim 1. It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to have the fusion protein of interest in the method of Upadhyay as modified by Shen or Ares be CTLA4-IgG having molecular weight less than 100 kda because
(1) as noted above, Upadhyay already does disclose that the fusion protein may comprise an antibody;
(2) Gray discloses, “Use of the CTLA4-immunoglobulin fusion proteins of the invention is applicable in a variety of situations, such as to inhibit transplant rejection or autoimmune reactions in a subject. In these situations, immunolobulin constant region-mediated biological effector mechanisms, such as complement-mediated cell lysis. Fc receptor-mediated phagocytosis or antibody-dependent cellular cytotoxicity, may induce detrimental side effects in the subject and are therefore undesirable.” See paragraph [0007]. So CTLA4-IgG is medially significant; and
(3) Gary also discloses that it is known to use electrophoresis to purify CTLA4-immunoglobulin fusion proteins using electrophoresis. See paragraph [0062].
So, to the fusion protein of interest in the method of Upadhyay as modified by Shen or Ares be CTLA4-IgG having molecular weight less than 100 kda is prima facie obvious as simple substitution of one known element (fusion protein of interest) for another to obtain predictable results. See MPEP 2143)I)(B).
Other Relevant Prior Art
The International Search Report for international application no. PCT/IB2022/062426 cites WO 2021/009669 A2 as a “Y” document against claims 1-12 of that application; an article by Geng et al., as a “Y” document against claims 1-3 and 5-12; US 2021/0230250 A1 as a “Y” document against claims 3 and 4; and Molecular probes online document (“Molecular Probes”) as a “Y” document against claim 4. Notwithstanding Information Disclosure Statement above, the Examiner has nevertheless considered these four “Y” documents.
Regarding WO 2021/009669 A2, it is the base reference in rejections under 35 U.S.C 103 above.
Regarding the article by Geng et al., there does not appear to be any mention of capillary electrophoresis or of a protein to SDS ratio.
Regarding US 2021/0230250 A1, there does not appear to be any mention of a protein to SDS ratio or even of SDS at all.
Regarding Molecular Probes there is no mention of capillary electrophoresis or of a protein to SDS ratio.
Asermely et al., “Identification of a recombinant synaptobrevin-thioredoxin fusion protein by capillary zone electrophoresis using laser-induced fluorescence detection,” Journal of Chromatography B, 695 (1997) 67-75 (hereafter “Asermely”) discloses4 an improved process for the separation of more than two low molecular weight proteins presents in a protein mixture (this may be inferred from the various electropherograms in the figures, such as Figures 1-3, as (1) the mixture includes lysates from E. coli cells (see 2.3.1 . Sample Preparation, which is on pages 68-69), and (2) the fluorophore used, CBQCA, is said to specifically label only primary amines, such as proteins (see the second full sentence in the right column on page 73 (“First, CBQCA . . . .”). So, the peaks in the electropherograms are expected to be protein peaks.), comprising
a) providing a protein mixture comprising at least an impurity (any protein corresponding to a peak other than the TSB-51 peak in Figures 1-3) and the protein of interest (synaptobrevin-thioredoxin fusion protein (TSB-51) (see the title)), wherein the protein mixture does not contain a full-length antibody having molecular weight about 150 kda (there is no indication that an antibody was used at all in any of the experiments);
b) mixing the protein mixture at a suitable ratio with sodium dodecyl sulphate or SDS5 to form a treated protein mixture;
d) injecting the protein mixture into a CE-instrument (see the second sentence of 2.4. Effect of voltage on the migration time of TSB-51, which is on page 69);
e) performing CE-SDS by injecting the treated protein mixture in a CE-instrument (see 2.4. Effect of voltage on the migration time of TSB-51, which is on page 69); and
f) separating more than two low molecular weight proteins (this step may be inferred from the electropherograms in Figures 1-3, noting how the TSB-51 peak is separate from the other protein peaks.).
However, in contrast to claim 1 while SDS was used during PAGE )(polyacrylamide gel electrophoresis), no SDS was used during the capillary electrophoresis. See in Asermely 2.3.2 Capillary zone electrophoresis, which is on page 69, and 3.6. SDS-PAGE gels and Edman sequencing, which is on pages 72-73.
Allowable Subject Matter
Claim 4 would be allowable if rewritten or amended to overcome the rejections under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action.
The following is a statement of reasons for the indication of allowable subject matter:
a) in claim 4 the combination of limitations requires the following underlined limitations
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as a first matter,
(1) the scope of the phrase “low molecular weight impurities ” is vague. Although Applicant has a definition of “low molecular weight” in his specification this definition defines the phrase relative to “fusion protein” and “product-related impurities”, which are nowhere in the claim. Moreover, there is no clear explicit or implicit molecular weight range for low molecular weight. So, it is not clear how Applicant’s definition of “low molecular weight” limits the scope of the phrase “low molecular weight impurities ” in claim 4;
(2) the Examiner assumes that the phrases “about 80kda…”, “about 45 kda…”, and “about 25 kda to 30 kda…” are meant to indicate molecular weight values or a molecular weight range; and
(3) the claim clause “wherein the first, second, third and fourth LMWs are separated by CE-SDS…” is being interpreted as a product-by-process limitation. As such the claim is not limited to the manipulation of the recited step, only the structure (here actually composition) implied by the step. See MPEP 2113.
Nevertheless, in contrast to clam 4, even if high molecular weight protein (HMW) in Upadhyay as modified by Shen or Ares could be also be broadly construed as Applicant’s low molecular weight impurities along with LMW of Upadhyay, there is no suggestion of a composition of protein mixture wherein a first LMW has a MW about 80 kda, a second LMW has a MW about 45 kda, and a third and a fourth LMW each with a MW within about 25 kda to about 30 kda.
In contrast to claim 4, Bai et al. CN 109678969 A based on an EPO machine-generated English language translation (hereafter “Bai”) discloses a purifying method of CTLA4 (Cytotoxic T Lymphocyte-associated Antigen 4)-Ig (Immunoglobulin) fusion protein. See the Bai title. Bai further discloses that the CTLA4-IgG fusion proteins may initially be in a composition of protein mixture comprising “ various pollutants such as host protein (HCP), residual protein A, DNA, multimer, and low sialic acid protein, . . . .”; however, there is no suggestion of a composition of protein mixture wherein a first LMW has a MW about 80 kda, a second LMW has a MW about 45 kda, and a third and a fourth LMW each with a MW within about 25 kda to about 30 kda.
In contrast to claim 4, Leister et al. US 2009/0252749 A1 (hereafter “Leister”) discloses a composition of protein mixture comprising CTLA-IgG fusion protein that may comprise several LMWs and purifying the composition. See the Abstract and paragraphs [0477], [0478], [0485]-[0488], [0507], [0963], and [0976]. However, there is no suggestion of a composition of protein mixture wherein a first LMW has a MW about 80 kda, a second LMW has a MW about 45 kda, and a third and a fourth LMW each with a MW within about 25 kda to about 30 kda.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER STEPHAN NOGUEROLA whose telephone number is (571)272-1343. The examiner can normally be reached on Monday - Friday 9:00AM-5:30 PM EST.
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/ALEXANDER S NOGUEROLA/ Primary Examiner, Art Unit 1795
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See Applicant’s originally filed specification page 8.
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See Applicant’s originally filed specification page 8.
3 The Examiner understands this percentage range to be a w/v % range, so 1 to 10% w/v.
4 As a first matter the scope of the phrase “low molecular weight proteins ” is vague. Although Applicant has a definition of “low molecular weight” in his specification this definition defines the phrase relative to “fusion protein” and “product-related impurities”, which are nowhere in the claim. So, it is not clear how Applicant’s definition of “low molecular weight” limits the scope of the phrase “low molecular weight proteins ” in claim 1.
5 Note that the phrase “sodium dodecyl sulphate or SDS” is redundant as Applicant’s specification,
page 7, line 17, states, ‘The term "SDS" refers to Sodium dodecyl sulfate.’