DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claim Status
Claims 61-67, 69-95, and 105-119 are pending; claim 61 was amended. Claims 71-76, 80-82, 84-89, 91-95, 108, 110-111, 114, and 117-118 are withdrawn. Claims 61-67, 69-70, 77-79, 83, 90, 105-107, 109, 112-113, 115-116, and 119 are presently considered.
Election/Restrictions
Applicant's election with traverse of the originally elected species as described in Example 1b (in the reply filed on 10/01/2020 was previously acknowledged, and the requirement was deemed proper for reasons of record and was previously made Final.
The originally elected species, as identified in the Action mailed 12/15/2020 at pages 2-5, was previously deemed free of the prior art for reasons of record (see, e.g., Non-Final mailed 12/15/2020 at pages 2-5). However, the amendments filed 9/19/2023 and entered on 10/10/2023 overcame the rejection in view of a non-elected species (see, e.g., MPEP § 803.02(III)(A)), but have also necessitated a denial of priority and a rejection for new matter (see below). Accordingly, the originally elected species has been examined again with respect to newly available prior art over the intervening years of Dec. 18, 2009, to June 28, 2019 (see Denial of Priority, below). Accordingly, the originally elected species has been reexamined in view of newly available prior art.
Upon review of Example 1, Example 1b, and Table 1 of the original disclosure, the originally elected species is understood to be the species of process involving the following elements and steps:
A recombinant FIX-(human Albumin) fusion protein as described in WO 2007/144173 (cited in IDS filed 10/25/2019 as cite No. 12) was expressed in CHO cells (see, e.g., Spec. filed 6/28/2019 at 50 at Example 1 at lines 5-11);
The fermentation culture was subjected to filtration through a “Cuno Zeta 60SP followed by 10SP” to yield clarified cell culture fluid (see, e.g., Spec. filed 6/28/2019 at 50 at Example 1 at lines 5-11);
“To the clarified cell culture fluid EDTA was added to” 35 mM (see, e.g., Spec. filed 6/28/2019 at 51 at Example 1b at lines 9-13);
A “loading fluid” comprising “20 mM Tris, pH 7.0 plus EDTA at” 35 mM was made (see, e.g., Spec. filed 6/28/2019 at 51 at Example 1b at lines 9-13 and 20-22);
The “loading fluid” was applied to an anion exchange column packed with POROS® HQ 50, which had been equilibrated using “equilibration fluid” containing 50 mM MES, 100 mM NaCl, and 50 mM disodium-EDTA, and having a pH of 5.0 (see, e.g., Spec. filed 6/28/2019 at 51 at Example 1b at lines 20-26);
After applying the “loading fluid”, the column was washed with a “first washing fluid” consisting of 50 mM MES, 100 mM NaCl, and 50 mM disodium-EDTA, wherein the first washing fluid pH was 5.0 (see, e.g., Spec. filed 6/28/2019 at 51 at Example 1b at lines 26-31).
After the first wash, a second wash for “[f]urther contaminants, less strongly bound than the rIX-FP” was performed using a “second washing fluid” consisting of 50 mM MES, 195 mM NaCL, 2 mM CaCl2, wherein the second washing fluid had a pH of 5.0 (see, e.g., Spec. filed 6/28/2019 at 51 at Example 1b at lines 30 to page 52 at line 2).
After the second wash, the column was subjected to “re-equilibration” using an “first re-equilibration fluid” consisting of 50 mM Tris-HCL, 100 mM NaCl, and having a pH of 8.5 (see, e.g., Spec. filed 6/28/2019 at 52 at lines 2-4);
After the “first re-equilibration”, the column was subjected to a second “re-equilibration” using a “second equilibration fluid” consisting of 50 mM Tris-HCL, 100 mM NaCl, 10 mM CaCl2, and having a pH of 8.5 (see, e.g., Spec. filed 6/28/2019 at 52 at lines 3-6); and
After the “second re-equilibration”, the rIX-FP was then eluted from the column by applying an “elution fluid” consisting of 50 mM Tris-HCL, 150 mM NaCl, 30 mM CaCl2, and having a pH of 8.5 (see, e.g., Spec. filed 6/28/2019 at 52 at lines 4-10).
Accordingly, the single, originally elected species is understood to require at least these ten steps, performed in the order set forth above, on the specific protein identified. It is unclear which claims read upon the originally elected species, because all original claims (i.e., claims 30-60) were canceled in the Reply filed 4/20/2021. Critically, Applicant failed to identify the claims encompassing the elected species in the claims that were subsequently added (see, e.g., Requirement mailed 8/04/2020 at 4-5 at bridging ¶, noting that identification of claims encompassing the elected species is required, “including any claims subsequently added”). However, the originally elected species is understood to read upon instant claims 61-67, 69-70, 77-78, 79, 83, 90, 105-107, 109, 112-113, 115-116, and 119. If Applicant disagrees and believes the originally elected species, as presently claimed, reads upon additional claims, then those should be clearly and unambiguously identified in the next response.
Accordingly, upon review of the newly applicable intervening art, the originally elected species has been deemed clearly anticipated in view of the prior art of WO2011/073235 (June 23, 2011). Applicant is advised that the originally elected species appears identical in scope, and therefore any additional claims that are identified as reading upon the originally elected species by Applicant admission will also be presumed anticipated by WO’235 absent evidence to the contrary.
Per MPEP § 803.02(III)(A), claims to non-elected species are withdrawn, and examination of the pending claims has not been extended unnecessarily to cover all non-elected species encompassed by the pending claim scope. Accordingly, instant claims 71-76, 80-82, 84-89, 91-95, 108, 110-111, 114, and 117-118 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/15/2020.
Examination has not been extended beyond the elected species identified above per MPEP § 803.02. However, during search and examination, art pertinent to non-elected species was incidentally discovered; as a courtesy the incidentally discovered art has been set forth on record below. Upon amendment excluding the originally elected species from the pending claim scope, examination will be extended to additional non-elected species.
Accordingly, claims 61-67, 69-70, 77-78, 79, 83, 90, 105-107, 109, 112-113, 115-116, and 119 are presently considered.
Claim Interpretation
For purposes of applying prior art, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
Amended, independent claim 61 is representative of the newly pending claim scope. Amended claim 61 is directed to a process:
61. (Currently Amended) A process for the purification of a polypeptide produced by a cultured host cell, comprising:
providing a positively charged, anion-exchange chromatography matrix;
providing a chemical compound ;
adding to the matrix a Vitamin K-dependent polypeptide to be purified;
adding the chemical compound at a concentration of 15 mM to 200 mM to the matrix by one or more of the following steps, such that the chemical compound and the Vitamin K-dependent polypeptide compete for binding to the matrix:
(a) adding an equilibration fluid comprising the chemical compound to the matrix before the Vitamin K-dependent polypeptide is added to the matrix, such that at least part of the chemical compound binds to the matrix, and/or
(b) adding a loading fluid comprising the chemical compound and the Vitamin K dependent polypeptide to the matrix, such that at least part of the chemical compound and at least part of the Vitamin K-dependent polypeptide compete for binding to the matrix, and/or
(c) after the Vitamin K-dependent polypeptide is added and bound to the matrix, adding one or more washing fluids comprising the chemical compound to the matrix to wash the matrix, such that the chemical compound and the Vitamin K-dependent polypeptide continue to bind to the matrix, wherein the washing fluid has a pH and a conductivity to elute one or more impurities from the matrix while the matrix retains the Vitamin K-dependent polypeptide; and
eluting the Vitamin K-dependent polypeptide from the matrix using an elution fluid to form an eluate comprising one or more impurities, wherein the elution fluid has a pH and a conductivity to elute the Vitamin K-dependent polypeptide from the matrix;
thereby providing an increased ratio of the Vitamin K-dependent polypeptide to the one or more impurities in the eluate as compared to the same process where the chemical compound is not added to the matrix;
wherein the impurity comprises other polypeptides and/or DNA from the host cell; and
wherein the chemical compound is ethylene diamine tetraacetic acid (EDTA) or ethylene glycol tetraacetic acid (EGTA).
The applicable claim interpretation is provided below.
“Comprising” is an open-ended transitional term (see, e.g., MPEP § 2111.03(I)), wherein additional steps or components are not excluded. However, “‘[c]omprising’ is a term of art used in claim language which means that the named elements are essential” (see, e.g., id.; see also Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997)).
The genus of “vitamin K-dependent” polypeptides and proteins was described in the Claim Interpretation Section of the Action mailed 12/15/2020, which is incorporated herein (see, e.g., Action mailed 12/15/2020 at page 8, identifying a non-exhaustive list of eleven subgenera of such proteins). For purposes of the present examination, it is understood that Factor IX polypeptides are a type of “vitamin K-dependent” polypeptide (see, e.g., Spec. filed 6/28/2019 at 33 at lines 29-31; see also, instant claims 107, 109, and 112).
The genus of “chemical compound[s]” was amended in the Reply filed 9/19/2023 (and entered in the RCE filed 10/10/2023) to exclude all other embodiments besides EDTA and EGTA (i.e., the limitations of dependent claim 96 were incorporated into independent claim 61, and claim 96 was canceled)
Amended claim 61 recites the requirement
...adding the chemical compound at a concentration of 15 mM to 200 mM to the matrix by one or more of the following steps...
Accordingly, the phrase “one or more” is understood to mean that the chemical compound may be present in steps (a); (b); (c); (a) and (b); (a) and (c); (b) and (c); or present in all three steps.
Amended claim 61 contains the following phrases:
....such that the chemical compound and the Vitamin K-dependent polypeptide compete for binding to the matrix...
..... such that at least part of the chemical compound binds to the matrix....
.... such that at least part of the chemical compound and at least part of the Vitamin K-dependent polypeptide compete for binding to the matrix....
..... such that the chemical compound and the Vitamin K-dependent polypeptide continue to bind to the matrix......
..... thereby providing an increased ratio of the Vitamin K-dependent polypeptide to the one or more impurities in the eluate as compared to the same process where the chemical compound is not added to the matrix.
Each of these phrases is understood to be a recitation of an intended or expected result fully satisfied by the performance of the positively recited method steps set forth at newly added claim 61 (see, e.g., MPEP § 2111.04(I), noting that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited’"). This is reasonable, because no structure/function limitations commensurate in scope with such phrases appear in the originally filed disclosure, and therefore such phrases are not reasonably interpreted as functional limitations, but instead as “whereby” clauses (see, e.g., MPEP § 2111.04(I)).
Claim 61 was amended following the Final mailed 6/18/2021 to include the phrase:
....providing a positively charged, anion-exchange chromatography matrix;
As noted in the prior action, the matrix is reasonably inferred to be an “anion-exchange chromatography matrix”, which is reasonably inferred to have a solid phase support matrix that is positively charged (see, e.g., Spec. filed 6/28/2019 at 4 at lines 19-22, 18 at lines 21-30). Therefore, the amendment does not further limit the claim scope because anion-exchange chromatography is understood to utilize a positively charged matrix to capture negatively charged molecules of interest. Therefore, the phrase are reasonably understood to make explicit that an AXC matrix is positive.
“[A]bout” has appeared in prior claim sets. The original disclosure identifies that the term “about” is “used to indicate that a value includes the inherent variation of error for the device and the method being employed…” (see, e.g., Spec. filed 6/28/2019 at 12 at line 28 to page 13 at line 2), but this definition fails to actually identify what the numerical error of the Applicant’s methods and equipment were (i.e., different equipment has different levels of precision and accuracy). Therefore, it is unclear if “about” as used in the claims and original disclosure may reasonably indicate variances of ±1%, ±5% , ±10%, ±20, etc. For purposes of claim interpretation, the “about” has been reasonably understood to indicate a variability of ±20% or more of a given number unless otherwise specified.
At all claims, references to “the matrix” are reasonably understood to refer to the “anion-exchange chromatography matrix” as recited at claim 61 at line 2.
At all claims, “the chemical compound” is reasonably understood to refer to either EDTA or EGTA as recited at amended claim 61.
At amended claim 61, the term “host cell” is not explicitly defined, but is reasonably understood to be derivable from a “host” (see, e.g., Spec. filed 6/28/2019 at 17 at lines 9-12), wherein “[t]he host cell can be any cell that is capable of expressing the target polypeptide” (see, e.g., Spec. filed 6/28/2019 at 32 at lines 20-30; see also id. at 43 at lines 15-22, discussing host cells derived from multicellular organisms). Accordingly, a “host cell” is given the broadest reasonable interpretation, and is reasonably understood to encompasses any “cell that is capable of expressing the target polypeptide”, including the cells of a genetically modified organism.
In the Reply filed 9/19/2023 and entered in the RCE filed 10/10/2023, claim 61 was amended to recite and require “a polypeptide produced by a cultured host cell”. Although the term “host cell” can broadly refer to transgenic host cells and organisms in the relevant art (see, e.g., US2009/0214528 at ¶[0037]), the term “cultured” is understood to exclude tissue cultures and in vivo host cells from the pending claim scope (see id). This interpretation was confirmed by the Applicant in the Response filed 2/01/2024, wherein Applicant noted that “‘cultured host cell’ is understood as any cell that is cultured in vitro (i.e., outside a living organism) and capable of expressing the polypeptide of interest” (see, e.g., Reply filed 2/01/2024 at 12 at 1st partial ¶).
Additional claim interpretations are provided below.
Withdraw Claim Rejections
The traversal of the Denial of Priority filed 2/01/2024 (see, e.g., Reply filed 2/01/2024 at § III on pages 10-13) is persuasive in part. However, the proffered arguments have not overcome the entire basis for denial of priority. A revised denial of priority is set forth below.
Denial of Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, 13/516,740 (filed 2/03/2013) and 14/813,461 (filed 7/30/2015) fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
The MPEP states that "[w]hile there is no in haec verba requirment, . . . . claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP § 2163.
Lack of Express Support
Claim 61 is representative of the pending claim scope. Claim 61 does not literally appears in App’740, App’461, or any priority document and therefore the claims lack literal support in these priority documents. The disclosures of App’740 and App’461 are representative of the disclosures of the priority documents.
Specifically, the disclosures of App’740 and App461 each fail to teach or disclose the use of 15 mM to 200 mM of EGTA as now claimed and recited.
Accordingly, each of App’740 and App’461 fail to provide literal support for the pending claim scope that is synonymous or equivalent in scope.
Lack of Implicit or Inherent Support
The MPEP states that "[w]hile there is no in haec verba requirment, . . . . claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP § 2163.
Per MPEP § 2163(I)(B), “[a]n amendment to correct an obvious error does not constitute new matter where the ordinary artisan would not only recognize the existence of the error in the specification, but also recognize the appropriate correction. In re Oda, 443 F.2d 1200, 170 USPQ 268 (CCPA 1971)”. Here, no allegation that the amendments correct an obvious error has been made. Furthermore, upon inspection, Examiner is unable to identify any single “obvious error” that would lead to instantly amended claim 61 and the scope thereof. Accordingly, the amendments cannot be said to merely correct an obvious error.
Upon review, the Examiner no disclosure pertaining to the usage of EGTA at the specific range of 15 mM to 200 mM as presently claimed has been identified in either of App’740 and App’461.
Accordingly, the amended claim scope is not literally, inherently, or implicitly supported by the originally filed disclosure.
Accordingly, App’740 and/or App’461 each fail to provide implicit or inherent support for the pending claim scope that synonymous or equivalent in scope, or otherwise commensurate in scope with the pending claims.
Conclusion
Accordingly, priority to US Application 13/516,740 (filed 2/03/2013) and US Application 14/813,461 (filed 7/30/2015) is denied for claim 61 and all of the dependents of those claims; these claims have been accorded a priority date of 6/28/2019, which corresponds to the filing date of instant US Application No. 16/455,856 (filed 6/28/2019).
The AIA -indicator has not been changed because the issues impacting priority identified above have been identified as new matter as explained in a subsequent rejection below.
Response to Arguments Regarding Denial of Priority
Applicant's arguments filed 2/01/2024 have been fully considered but they are not persuasive to rebut the denial of priority.
The traversal was persuasive in part, with respect to the “cultured host cell” (see, e.g., Reply filed 2/01/2024 at § III on pages 10-13), and Examiner thanks Applicant for identifying a supporting disclosure. The denial of priority has been revised to remove all portions pertaining to this issue. However, the concentration range of EGTA remains.
It is the Examiner’s position that instant claim 61 is not supported by either App’740 or App’461 at least on the basis that the range of “15 mM up to 200 mM” of EGTA is not literally, inherently, or implicitly disclosed (see, e.g., Denial of Priority, above). It is the Examiner’s understanding that Applicant disputes this by alleging that it would have been obvious that a separate and distinct disclosure reciting only EDTA could be extended to EGTA, although such disclosure did not literally or inherently recite EGTA (see, e.g., Reply filed 2/01/2024 at 12 at final ¶), but instead the portion relied upon by the Applicant literally identifies that the disclosed amounts are “For EDTA” (see, e.g., EP09015707.4 at 30 1-12). Therefore, this argument suggesting such amounts are “obvious” are not persuasive because obviousness is not the test for written description:
[A]n applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention" (see, e.g., Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398, emphasis added).
Therefore, although the originally-filed disclosure may, at best, render the instant claims obvious, “a description which renders obvious a claimed invention is not sufficient to satisfy the written description requirement of that invention” (see, Regents of the University of California v. Eli Lilly, 119 F.3d 1559, 1567 (Fed. Cir. 1997)) because “[o]ne shows that one is ‘in possession’ of the invention by describing the invention, with all its claimed limitations, not that which makes it obvious” (Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1571-72 (Fed. Cir. 1997) at 1572). Here, the only evidence Applicant proffers is a reference to a different chemical compound, which is not EGTA (see, e.g., Reply filed 2/01/2024 at 12 at final ¶). Accordingly, suggesting that an exact concentration range for an exact chemical compound is “obvious” in view of a disclosure pertaining to a different chemical compound is insufficient to establish a supporting disclosure commensurate in scope with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112.
Accordingly, the denial of priority is maintained.
Maintained or Revised Rejections
Claim Rejections - 35 USC § 112(a), New Matter
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 61-67, 69-70, 77-79, 83, 90, 105-107, 109, 112-113, 115-116, and 119 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim Scope
All examined claims depend directly or indirectly upon claim 61, which is representative of the pending claims scope.
Brief Summary of the Issue
The pending claim scope has been repeatedly narrowed and amended in a manner resulting in the pending claims being directed to a previously unspecified subgenus, which is not described with specificity commensurate in scope with the requirements of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, in the originally filed disclosure.
Lack of literal Support
The MPEP states that "[w]hile there is no in haec verba requirment, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP 2163.
Amended claim 61 does not literally appear in the originally filed disclosure. For example, the term “cultured host cell” is undefined on record and fails to literally appear on record. In addition, the original disclosure fails to teach or disclose the use of 15 mM to 200 mM of EGTA as now claimed, and therefore the claimed range of 15 mM to 200 mM of EGTA is not literally taught or disclosed in the originally filed disclosure.
Accordingly, the amended claim scope is not literally supported by the originally filed disclosure.
Lack of Implicit or Inherent Support
The MPEP states that "[w]hile there is no in haec verba requirment, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP 2163. As noted above, the claims are not literally supported by the originally filed disclosure. Accordingly, the relevant issue is whether or not the new amendments and resulting claim scope is implicitly or inherently supported by the originally filed disclosure.
Per MPEP § 2163(I)(B), “[a]n amendment to correct an obvious error does not constitute new matter where the ordinary artisan would not only recognize the existence of the error in the specification, but also recognize the appropriate correction. In re Oda, 443 F.2d 1200, 170 USPQ 268 (CCPA 1971)”. Here, no allegation that the amendments correct an obvious error has been made. Furthermore, upon inspection, Examiner is unable to identify any single “obvious error” that would lead to instantly amended claim 61 and the scope thereof. Accordingly, the amendments cannot be said to merely correct an obvious error.
Upon review, the Examiner has determined that the closest supporting disclosure regarding the range appears in the Specification at pages 31-32 (see, e.g., Spec. filed 6/28/2019 at 31 at line 23 to page 32 at line 5). However, this disclosure pertains to EDTA but not EGTA. Accordingly, there is no implicit or inherent support for the instant claim scope, wherein EGTA is administered as claimed at a range of 15 mM to 200 mM.
Accordingly, the amended claim scope is not literally, inherently, or implicitly supported by the originally filed disclosure.
Applicant-identified Supporting Passages
In the Reply filed 9/19/2023, Applicant directed Examined to multiple disjointed passages and alleged that such passages provided support for the amended claim scope (see, e.g., Reply filed 9/19/2023 at 10 at § I). Upon review, Examiner notes that zero disclosures inherently, implicitly, or literally support the amended claim scope as an integrated whole1. For example, zero disclosures literally, implicitly, or inherently provide a term synonymous or equivalent in scope to “cultured host cell” as an integrated whole in a method as presently claimed. Furthermore, zero disclosures literally, implicitly, or inherently disclose a method as presently claimed using 15 mM to 200 mM of EGTA. Although the Specification discloses this range for EDTA (see, e.g., Spec. filed 6/28/2019 at 31 at line 23 to p. 32 at line 5), it does not identify the range as meaningful or applicable to EGTA, which is not EDTA.
At best, Applicant may be attempting to allege that such disclosures pertaining to EDTA render such ranges “obvious” for use with EGTA (see, e.g., Spec. filed 6/28/2019 at 31 at line 23 to p. 32 at line 5). However, obviousness is not the test for written description:
[A]n applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention" (see, e.g., Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398, emphasis added).
Therefore, although the originally-filed disclosure may, at best, render the instant claims obvious, “a description which renders obvious a claimed invention is not sufficient to satisfy the written description requirement of that invention” (see, Regents of the University of California v. Eli Lilly, 119 F.3d 1559, 1567 (Fed. Cir. 1997)) because “[o]ne shows that one is ‘in possession’ of the invention by describing the invention, with all its claimed limitations, not that which makes it obvious” (Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1571-72 (Fed. Cir. 1997) at 1572).
Additional Considerations
Upon review, it is the Examiner’s position that the pending claims, ostensibly directed to a subgenus, have arisen from multiple amendments from a much broader disclosure. Therefore, this raises a substantial and material concern, namely whether or not the subgenus presently claimed is adequately described in the originally filed disclosure. This is pertinent because the test for written description is not whether or not an artisan can retroactively “carve” out a genus by selectively picking some limitations while selectively ignoring other limitations (see, e.g., Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1328, 56 USPQ2d 1481, 1487 (Fed. Cir. 2000), stating that "[t]here is therefore no force to Purdue’s argument that the written description requirement was satisfied because the disclosure revealed a broad invention from which the [later-filed] claims carved out a patentable portion"). As noted in Indivior UK Ltd., “[a] written description sufficient to satisfy the requirement of the law requires a statement of an invention, not an invitation to go on a hunting expedition to patch together after the fact a synthetic definition of an invention” (see, e.g., Indivior UK Ltd. v. Dr. Reddy's Labs. S.A., 18 F.4th 1323, 1329 (Fed. Cir. 2021)).
In the instant case, the original description and the original claim scope were very broad. For example, the originally filed disclosure broadly identified that the “host cell can be any cell that is capable of expressing the target polypeptide” (see, e.g., Spec. filed 6/28/2019 at 32 at lines 23-26), taught that the “chemical compound” included >millions of compounds (see, e.g., Spec. filed 6/28/2019 at 29 at line 7 to page 32 at line 12, original claim 1 filed 6/28/2019; claim 30 as filed 6/29/2019, noting the functionally-defined genus of all “chemical compounds” “with the ability to complex metal ions” at the original claims); wherein the original disclosure identified methods in a combinatorial manner wherein the equilibration fluid, loading fluid, and washing fluid are ostensibly unlimited in scope and could comprise a vast and highly varied amount of various buffers, salts, and additional compounds (see id); and further informed artisans that such methods could be used with any “polypeptide of interest” (see, e.g., Spec. filed 6/28/2019 at 17 at lines 19-31, original claim 1 filed 6/28/2019; claim 30 as filed 6/29/2019, noting that the disclosure and original claims are not limited to “Vitamin K-dependent polypeptides”, which is “not intended to be a limiting recitation”). Accordingly, from a combinatorial perspective, the disclosure sets forth a “laundry list” style disclosure from which Applicant is now attempting to “carve out” a patentable subgenus by taking disjointed disclosures that are “patch[ed] together after the fact”. However, the courts have previously addressed situations wherein an artisan discloses a “laundry list” disclosure and subsequently attempts to combine various portions of the disclosure to arrive at a novel subgenus (see Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1328, 56 USPQ2d 1481, 1487 (Fed. Cir. 2000), stating that "[t]here is therefore no force to Purdue’s argument that the written description requirement was satisfied because the disclosure revealed a broad invention from which the [later-filed] claims carved out a patentable portion"). Similarly, in this case, selectively picking and choosing some limitations from disjointed portions of the disclosure while selectively ignoring other limitations amounts to an attempt to “carve[] out a patentable portion” of the original disclosure and fails to satisfy 35 USC 112(a). Although the Specification does disclose a “laundry list” of possibilities, the mere disclosure of “each ... individual limitations” separately and distinctly, does not evidence possession of all combinations of all such limitations “as an integrated whole” because written description support requires more than the combination of “an amalgam of disclosures plucked selectively from the ... application” (see, e.g., Novozymes A/S v. DuPont Nutrition Biosciences APS, 723 F.3d 1336, 1349, 107 U.S.P.Q.2d 1457, 1467, 2013 BL 192990, 14 (Fed. Cir. 2013), explaining that the written description analysis requires “[t]aking each claim . . . as an integrated whole rather than as a collection of independent limitations”). Here, the original specification provided a vast and highly varied genus, and only a very limited number of examples were even reduced to practice, and the limited examples reduced to practice appear to be highly similar with respect to steps, buffers, concentration ranges, etc. Accordingly, "Whatever may be the viability of an inductive-deductive approach to arriving at a claimed subgenus, it cannot be said that such a subgenus is necessarily described by a genus encompassing it and a species upon which it reads" (see also In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972)).
Accordingly, the instantly claimed subgenus is not reasonably described in the originally filed disclosure because the claimed subgenus has been impermissibly “carved out” from a “laundry list” disclosure, and only “patched together” by selectively picking (or ignoring) from among numerous disjointed disclosures set forth in the originally filed disclosure to create a “synthetic definition of an invention”, which was not fairly or reasonably identified or described with specificity in the originally filed disclosure (see also, Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1328, 56 USPQ2d 1481, 1487 (Fed. Cir. 2000), stating that "[t]here is therefore no force to Purdue’s argument that the written description requirement was satisfied because the disclosure revealed a broad invention from which the [later-filed] claims carved out a patentable portion").
Conclusion
Per MPEP § 2163, new or amended claims which introduce elements or limitations which are not supported by the as-filed disclosure violate the written description requirement (see, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971)). Here, the newly added claim limitations are not inherently, implicitly, or literally supported by the originally filed disclosure.
Therefore, amended claims 61-67, 69-70, 77-79, 83, 90, 105-107, 109, 112-113, 115-116, and 119 are rejected.
Response to Arguments Regarding 35 USC 112 and New Matter
Applicant's arguments filed 2/01/2024 have been fully considered but they are not persuasive to rebut the rejection.
The rejection has been revised to enhance clarity, but the basis of the rejection (i.e., the lack of literal, implicit, or inherent support for claim 61 and specifically the concentration range of EGTA remains unchanged).
Applicant traverses the rejection at pages 13-14 (see, e.g., Reply filed 2/01/2024 at §IV on 13-14), and the applicable arguments are addressed below.
It is the Examiner’s position that instant claim 61 comprises new matter at least because the disclosure of “15 mM up to 200 mM” of EGTA is not literally, inherently, or implicitly disclosed (see rejection, above). It is the Examiner’s understanding that Applicant disputes this by alleging that it would have been obvious that a separate and distinct disclosure explicitly reciting only EDTA would have rendered obvious such concentration ranges for the different chemical compound of EGTA (see, e.g., Reply filed 2/01/2024 at §IV on 13-14; see esp. id. at 14 at 1st ¶). Applicant does not dispute that the range of “15 mM up to 200 mM” of EGTA is not literally, inherently, or implicitly disclosed (see rejection, above). The references recited by Applicant literally limit the disclosure to EDTA and explicitly recite “For EDTA the preferred concentration for processes according to the invention are. . . .” (see, e.g., Reply filed 2/01/2024 at 14 at 1st ¶; see also Spec. filed 6/28/2019 at 31 at lines 22-25, emphasis added). Applicant fails to identify any disclosure identifying that the disclosed “preferred” concentration ranges “For EDTA” were applicable to any other compound. Accordingly, this is reasonably understood to be an argument alleging that such concentrations fort EGTA “would have been obvious”. Therefore, this argument suggesting such amounts are “obvious” are not persuasive because obviousness is not the test for written description:
[A]n applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention" (see, e.g., Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398, emphasis added).
Therefore, although the originally-filed disclosure may, at best, render the instant claims obvious, “a description which renders obvious a claimed invention is not sufficient to satisfy the written description requirement of that invention” (see, Regents of the University of California v. Eli Lilly, 119 F.3d 1559, 1567 (Fed. Cir. 1997)) because “[o]ne shows that one is ‘in possession’ of the invention by describing the invention, with all its claimed limitations, not that which makes it obvious” (Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1571-72 (Fed. Cir. 1997) at 1572). Here, the only evidence Applicant proffers is a reference to a different chemical compound, which is not EGTA (see, e.g., Reply filed 2/01/2024 at 14 at 1st ¶). Accordingly, suggesting that an exact concentration range for an exact chemical compound is “obvious” in view of a disclosure pertaining to a different chemical compound is insufficient to establish a supporting disclosure commensurate in scope with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112.
Accordingly, the rejection is maintained as revised above.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
Claims 61-67, 69-70, 77-79, 83, 90, 105-107, 109, 112-113, 115-116, and 119 are rejected under pre-AIA 35 U.S.C. 102(b) as being clearly anticipated by WO2011/073235 (June 23, 2011).
Claim interpretation: The applicable claim interpretation has been set forth in a separate section above, which is incorporated into the instant rejection. Additional claim interpretations are set forth below. Examiner notes the Denial of Priority, above, and notes that the Applicable filing date is 6/28/2019; therefore, WO2011/073235, published June 23, 2011, is applicable as intervening art that was published over a year prior to the applicable filing date of June 28, 2019. Applicant is advised that in the case where the Applicant believes that the Examiner misidentified a claim as not reading upon the originally elected species incorrectly, all claims identified as reading upon the originally elected species are understood to be rejected below in view of the disclosure of WO’235, which is identical to the originally elected invention, absent evidence to the contrary.
Regarding claims 61-67, 69-70, 77-79, 83, 90, 105-107, 109, 112-113, 115-116, 119, and all claims reading upon the originally elected species, WO’235 is understood to fully disclose and teach the originally elected species (compare originally elected species of Example 1b in the Spec. filed 6/28/2019 at 51 at line 6 to page 56 at line 4 with WO’235 at 51 at line 6 to page 56 at line 4, showing identical disclosure), because the disclosures pertaining to the originally elected species are identical.
Upon review and comparison of WO’235 with the originally elected species, both documents are understood to teach and disclose Example 1, Example 1b, Table 1, and the species as follows:
A recombinant FIX-(human Albumin) fusion protein was expressed in CHO cells (Compare WO’235 at 50 at Example 1 at lines 5-11 with Spec. filed 6/28/2019 at 50 at Example 1 at lines 5-11);
The fermentation culture was subjected to filtration through a “Cuno Zeta 60SP followed by 10SP” to yield clarified cell culture fluid (Compare WO’235 at 50 at Example 1 at lines 5-11 with Spec. filed 6/28/2019 at 50 at Example 1 at lines 5-11);
“To the clarified cell culture fluid EDTA was added to” 35 mM (Compare WO’235 at 51 at Example 1b at lines 1-13 with Spec. filed 6/28/2019 at 51 at Example 1b at lines 9-13);
A “loading fluid” comprising “20 mM Tris, pH 7.0 plus EDTA at” 35 mM was made (Compare WO’235 at 51 at Example 1b at lines 9-22 with Spec. filed 6/28/2019 at 51 at Example 1b at lines 9-13 and 20-22);
The “loading fluid” was applied to an anion exchange column packed with POROS® HQ 50, which had been equilibrated using “equilibration fluid” containing 50 mM MES, 100 mM NaCl, and 50 mM disodium-EDTA, and having a pH of 5.0 (Compare WO’235 at 51 at Example 1b at lines 9-26 with Spec. filed 6/28/2019 at 51 at Example 1b at lines 20-26);
After applying the “loading fluid”, the column was washed with a “first washing fluid” consisting of 50 mM MES, 100 mM NaCl, and 50 mM disodium-EDTA, wherein the first washing fluid pH was 5.0 (Compare WO’235 at 51 at Example 1b at lines 9-31 with Spec. filed 6/28/2019 at 51 at Example 1b at lines 26-31).
After the first wash, a second wash for “[f]urther contaminants, less strongly bound than the rIX-FP” was performed using a “second washing fluid” consisting of 50 mM MES, 195 mM NaCL, 2 mM CaCl2, wherein the second washing fluid had a pH of 5.0 (Compare WO’235 at 51 at Example 1b at line 9 to p. 52 at line10 with Spec. filed 6/28/2019 at 51 at Example 1b at lines 30 to page 52 at line 2).
After the second wash, the column was subjected to “re-equilibration” using an “first re-equilibration fluid” consisting of 50 mM Tris-HCL, 100 mM NaCl, and having a pH of 8.5 (Compare WO’235 at 51 at Example 1b at line 9 to p. 52 at line10 with Spec. filed 6/28/2019 at 52 at lines 2-4);
After the “first re-equilibration”, the column was subjected to a second “re-equilibration” using a “second equilibration fluid” consisting of 50 mM Tris-HCL, 100 mM NaCl, 10 mM CaCl2, and having a pH of 8.5 (Compare WO’235 at 51 at Example 1b at line 9 to p. 52 at line10 with Spec. filed 6/28/2019 at 52 at lines 3-6); and
After the “second re-equilibration”, the rIX-FP was then eluted from the column by applying an “elution fluid” consisting of 50 mM Tris-HCL, 150 mM NaCl, 30 mM CaCl2, and having a pH of 8.5 (Compare WO’235 at 51 at Example 1b at line 9 to p. 52 at line10 with Spec. filed 6/28/2019 at 52 at lines 4-10).
Accordingly, the pending claims are clearly anticipated with respect to the originally elected species.
Accordingly, claims 61-67, 69-70, 77-79, 83, 90, 105-107, 109, 112-113, 115-116, 119, and all claims reading upon the originally elected species are rejected as anticipated by the prior art.
Response to Arguments Regarding 35 USC 102
Applicant's arguments filed 2/01/2024 have been fully considered but they are not persuasive. Applicant traverses the rejection by alleging that WO’235 does not constitute prior art because the instant claims are allegedly entitled to a priority date of December 18, 2009 (see, e.g., Reply filed 2/01/2024 at § V on 14-15; see esp. id. at 14-15 at bridging ¶, 15 at 1st full ¶). This is not persuasive because priority to App’740 and App’461 have been denied, and therefore the effective filing date and priority date for the instant claims is 6/28/2019 which corresponds to the filing date of instant US Application No. 16/455,856 (filed 6/28/2019). Accordingly, such arguments are not persuasive.
Therefore, the rejection is maintained.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 61-62, 77-79, 83, 90, 107, 109, 112, and 115-116 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over US2008/0207879 A1 (Artur et al.; Aug. 28, 2008; cited in previous action) in view of WO 97/42835 (Nov. 20, 1997; Kutzko et al.; cited in IDS filed 10/25/2019 as cite no: 2).
Claim interpretation: The applicable claim interpretation has been set forth in a separate section above, which is incorporated into the instant rejection. Additional claim interpretations are set forth below.
Regarding instant claims [], and the purification of recombinant FIX from “cultured host cells”, US’879 teaches and reduces to practice a process for the purification of recombinant FIX from cell culture (compare US’879 at Example 5 at ¶¶[0137]-[0139], Tables VII-IX with instant claims 61, 73-74, 96). The exemplified process is understood to include the general steps of
loading a composition comprising a rFIX onto an anion exchange material,
washing the anion exchange material using a wash buffer which has a salt concentration of more than 200 mM,
eluting the rFIX from the anion exchange material using an elution buffer comprising divalent cations, and
collecting the eluate.
(see, e.g., US’879 at id.; see also id. at ¶¶[0013]-[0017], claims 1-7), and the process utilized a QFF Sepharose Anion Exchange resin (see, e.g., US’879 at ¶[0138]), and included the steps and buffers disclosed at Tables VII-VIII (see, e.g., US’879 at ¶¶[0138], Tables VII-VIII). Example 5 of US’879 discloses an equilibration buffer containing EDTA (see, e.g., US’879 at ¶¶[0137]-[0139], Tables VII-VIII). Accordingly, the equilibration buffer contains EDTA (see, e.g., US’879 at ¶¶[0137]-[0139], Tables VII-VIII; compare id. with instant claims 61-62 and 68). Regarding instant claims 61, 107, 109, 112 and the purification of the Vitamin K-dependent protein of Factor IX, US’879 pertains to methods for the purification of recombinant Factor IX using anion exchange chromatography (see, e.g., US’879 at title, abs), wherein it is understood that Factor IX (or “rFIX”) is a Vitamin K-dependent protein (see, e.g., US’879 at ¶¶[0003]-[0004], [0168]; see also claim interpretation section above). The use of human rFIX would be at once envisaged in view of the disclosure of rFIX (see, e.g., id.; see also id. at claims 1-2). Regarding instant claims 61-62 and step (a), at Example 5 of US’879, the equilibration buffer comprises EDTA (see, e.g., US’879 at ¶¶[0137]-[0139], Tables VII-VIII; compare id. with instant claims 61-62). Regarding the temperature of the process, US’879 reasonably identifies that the process was carried out at approximately 24.0°C to 24.9°C (see, e.g., US’879 at ¶¶[0137]-[0139], Tables VII-VIII; see esp. id. at Table VIII; note that “about” has been reasonably interpreted to mean ±20%, and therefore “about 25°C” includes 20-30°C). Regarding the equilibration fluid, US’879 discloses that the “equilibration buffer” comprised 20 mM Tris, 2 mM EDTA, had a pH of 7.4, and a conductivity of 2.11 mS/cm (see, e.g., US’879 at ¶¶[0137]-[0139], Tables VII-VIII). Regarding claims 77-79 and the loading fluid, US’879 discloses a “loading buffer” having a pH of 7.4, 2 mM of EDTA, 20 mM Tris, and a conductivity of 2.11 mS/cm (see, e.g., US’879 at ¶¶[0038]-[0051], [0054]-[0055] and ¶¶[0137]-[0139], Tables VII-IX, noting that the “loading buffer” is understood to be comparable/equivalent in pH, EDTA, Tris, Triton X-100, and conductivity as the equilibration buffer); accordingly the loading fluid contained Tris as required by claims 77-79. Notably, an anion Exchange resin purification process works by separating the desired rFIX protein from contaminants that are washed off (see, e.g., US’879 at ¶¶[0038]-[0051], [0054]-[0055] and ¶¶[0137]-[0139], Tables VII-IX; see esp. id. at ¶[0139], Table IX, Title of Example 5). Regarding claim 83 and the washing buffer, US’879 discloses a “wash buffer” that comprises 20 mM Tris, 220 mM NaCl, and has a pH of 7.46, and a conductivity of 22.1 mS/cm (see, e.g., US’879 at ¶¶[0137]-[0139], Tables VII-VIII). Regarding claims 90 and the elution fluid, US’879 discloses an initial “elution buffer” (“Gradient Buffer A”) comprising 20 mM Tris, 2 mM CaCl2, having a pH of 7.48, and a conductivity of 2.11 mS/cm (see, e.g., US’879 at ¶¶[0137]-[0139], Tables VII-VIII); and a second “elution buffer” (“Gradient Buffer B”) comprising 20 mM Tris, 2 mM CaCl2, 180 mM NaCl, having a pH of 7.40, and a conductivity of 18.6 mS/cm (see, e.g., US’879 at ¶¶[0137]-[0139], Tables VII-VIII). Regarding claims 115-116, each of the washing and elution buffers contain salt in an amount sufficient to adjust buffer ionic strength to some extent (see, e.g., US’879 at ¶¶[0137]-[0139], Tables VII-VIII, noting that the washing buffer contains NaCl, and the elution “Gradient” buffer B contains NaCl), and therefore claim 115 is reasonably deemed anticipated by Example 5 of US’879.
The prior art of US’879 differs from the instant claims as follows: US’879 at Example 5 does not explicitly teach or disclose the use of EDTA in the disclosed buffers at a concentration of “15 mM to 200 mM” as recited and required at amended claims 61 and 69-70. Although, US’879 does inform artisans that the concentration of EDTA may be raised up to 10 mM (see, e.g., US’879 at ¶¶[0047], [0054]), US’879 does not explicitly teach or disclose the use of higher concentrations of EDTA.
The usage of higher concentrations of EDTA were known in the protein purification arts: Like US’879, WO’835 also pertains to methods of purifying biologically active peptides (see, e.g., WO’835 at abs, claims 1-5, 9-13, 16-17, 19, and 21, and at pages 6 at lines 27-35, 9 at lines 30-34, 10 at lines 24-36, 11-12 at bridging ¶, 12 at lines 25-35, Fig. 1). However, WO’835 teaches, discloses, and informs artisans that “the addition of EDTA increased filterability at all pHs and at all concentrations tested” (see, e.g., WO’835 at 15 at lines 15-17), wherein WO’835 teaches and directs artisans to utilize EDTA at “approximately 20 to 50 mM”, and “[m]ost preferably” at “about 25 mM EDTA” (see, e.g., WO’835 at 10 at lines 5-9).
The usage of higher concentrations of EDTA in protein purification methods has known and expected benefits: An artisan would be motivated to utilize a higher amount of EDTA as described in WO’835 because WO’835 identifies that “the addition of EDTA increased filterability at all pHs and at all concentrations tested” (see, e.g., WO’835 at 15 at lines 15-17), wherein such increased filterability provides substantial expected and predicted benefits during purification, including (i) improving the flow of permeate (see, e.g., WO’835 at 4 at lines 30-35, p. 5 at lines 32-35), (ii) preventing fouling of filtration membranes (see, e.g., WO’835 at 9-10 at bridging ¶, p. 10 at lines 16-23, p. 12 at 7-21), and (iii) permitting recycling of filtration membranes and thereby “substantially reduc[ing] processing costs” for “large-scale purification” (see, e.g., WO’835 at 10 at lines 16-23, p. 12 at 7-21). Accordingly, an artisan would expect that higher levels of EDTA as taught and disclosed by WO’835 would enhance protein purification protocols by increasing filterability of biological samples from which a desired protein would be purified.
An artisan would have a reasonable expectation that increasing EDTA would enhance filterability of protein purification protocols, generally, because the disclosure of WO’835 is understood to be applicable to numerous forms of protein purification, including methods utilizing ion exchange chromatography, tangential flow filtration, etc. (see, e.g., WO’835 at 10-11 at bridging ¶, p. 12 at lines 28-35; see, e.g., WO’835 at Example 5 on 17, disclosing the use of an anion-exchange chromatography, a Q-Sepharose FF chromatography column).
An artisan would have a reasonable expectation that increasing EDTA would enhance the purification of Factor IX polypeptides, because WO’835 explicitly addresses and identifies that the disclosure was applicable to “human or non-human” proteins, including Factor IX polypeptides (see, e.g., WO’835 at 4 at lines 20-26, 6 at lines 27-35, 7 at line 34 to page 8 at line 5, claims 5 and 16). Accordingly, an artisan would readily appreciate that the disclosed methods and application of EDTA at “approximately 20 to 50 mM (see, e.g., WO’835 at 10 at lines 5-9) could desirably facilitate the purification of Factor IX from biological samples by predictably increasing the filterability of the sample as suggested by WO’835 (see, e.g., WO’835 at 15 at lines 15-17)
An artisan would have a reasonable expectation that EDTA could be added to either the loading fluid or the equilibration fluid in view of WO’835, because the presence of EDTA in loading fluids and equilibration fluids are explicitly exemplified (see, e.g., WO’835 at abs, at 10 at lines 6-10, claims 1-2 and 9-12, Example 1 on 13 at lines 1-35 and Example 2 on 15). Accordingly, an artisan would reasonably expect and predict that EDTA added to a loading fluid or equilibration fluid during a protein purification protocol would predictability enhance filterability and thereby provide beneficial results as taught and suggested by WO’835.
Regarding the impurities separated at claim 1, one of ordinary skill in the protein purification arts would readily appreciate that a protein of interest (see, e.g., WO’835 at Example 5 on 17, referencing Example 1 on pages 13-14, passim) is necessarily purified from all impurities present, including cellular matter (i.e., DNA, unwanted proteins, etc.) present in the original biological sample. Furthermore, the “wherein” phrase is understood to be a recitation of an intended or expected result fully satisfied by the performance of the positively recited method steps set forth at claim 61 (see, e.g., MPEP § 2111.04(I), noting that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited’"). Accordingly, the added “wherein” clause does not render the claim non-obvious.
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The claim is the obvious application (or substitution) of a known technique disclosed by WO’835 (i.e., the use of EDTA at 20 to 50 mM to enhance filterability of a biological sample in protein purification protocols) to improve the similar protein purification protocol of Factor IX as disclosed by US’879 in the same manner, wherein such application (or substitution) would simply increase the amount of EDTA utilized in the US’879 method to approximately 20-50 mM as suggested by WO’835, wherein such increased EDTA would expectedly and predictably yield a method for purifying Factor IX having increased filterability, increased flow, reduced membrane fouling, decreased processing costs, and purified Factor IX (see, e.g., MPEP § 2143(I)(B), (C), (D), and (F)).
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to utilize known purification methods (e.g., anion-exchange chromatography), with known chemical components (e.g., EDTA), at known concentrations utilized in the prior art (e.g., 20-50 mM), to achieve known and art-recognized benefits (e.g., improved purification efficiency, reduced fouling, and improved flow), in order to purify a known polypeptide of interest (e.g., Factor IX). Accordingly, in the absence of evidence to the contrary, an artisan would reasonably expect such methods as disclosed by the primary reference could successfully and predictably be utilized for the disclosed purpose of purifying Factor IX upon increasing the amount of EDTA utilized to about 20 to 50 mM. Such modifications are well-within the ordinary skill in the art.
No evidence of unexpected results commensurate in scope with the pending claims have been placed on record to date.
Accordingly, claims 61-62, 77-79, 83, 90, 107, 109, 112, and 115-116 are obvious in view of the prior art.
Response to Arguments Regarding 35 USC 103
Applicant's arguments filed 2/01/2024 have been fully considered but they are not persuasive. Applicant traverses the rejection at pages 15-19 (see, e.g., Reply filed 2/01/2024 at § VI at page 15 at final ¶ to page 19 at 1st full ¶). These arguments are addressed below.
It is the Examiner’s understanding that Applicant summarizes the rejection at pages 15-17 (see, e.g., Reply filed 2/01/2024 at § VI at page 15 at final ¶ to page 17 at 1st partial ¶). The summary fails to recapitulate the nuances of the rejection, and therefore the Examiner directs Applicant to the rejection, as set forth above. No arguments were raised in this portion of the response.
It is the Examiner’s understanding that Applicant traverses the rejection by alleging a lack of motivation (see, e.g., Reply filed 2/01/2024 at § VI.A at page 17 at 1st full ¶ to page 18 at 1st full ¶). In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the claim literally identifies multiple rationales supporting a determination of obviousness, including rationales under MPEP § 2143(I)(B), (C), (D), and (F). Applicant fails to acknowledge or address these rationales with specificity, and fails to dispute that the elements for each rationale have been fully satisfied. Accordingly, the Examiner’s rationales supporting a determination of obviousness are presently undisputed with specificity on record.
It is the Examiner’s understanding that Applicant traverses the rejection by repeating the difference statement of the rejection (see, e.g., Reply filed 2/01/2024 at page 18 at 1st partial ¶ at “(1)”. This is not persuasive because it is acknowledged by the Examiner as a difference, which is a requirement for rejections made under 35 USC 103 (see, e.g., MPEP § 2143). A difference must exist or the rejection would be made under 35 USC 102. Accordingly, acknowledging the existence of the difference statement required to formulate an obviousness rejection is insufficient to rebut an obviousness rejection.
It is the Examiner’s understanding that Applicant traverses the rejection by alleging that “Artur” alone does not teach the Applicant’s rationale for arriving at the claimed invention (see, e.g., Reply filed 2/01/2024 at page 18 at 1st partial ¶ at “(2)”). This is not persuasive for at least two reasons. First, in response to applicant's arguments against Artur alone, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Second, it is the Examiner’s understanding that Applicant mistakenly assumes that the Examiner’s rationale for arriving at the instantly claimed invention must be identical to the Applicant’s rationale (see, e.g., Reply filed 2/01/2024 at page 18 at 1st partial ¶ at “(2)”). This is incorrect. Per MPEP § 2144(IV), the Examiner may rely upon a rationale that differs from the Applicant’s rationale. In sum, such arguments are not persuasive.
It is the Examiner’s understanding that Applicant traverses the rejection by alleging that “Kutzko” alone does not teach “the use of EDTA during the purification process would have any impact on the purified product” (see, e.g., Reply filed 2/01/2024 at page 18 at 1st partial ¶ at “(3)”). This is not persuasive for at least two reasons. First, in response to applicant's arguments against Kutzko alone, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Second, it is the Examiner’s understanding that Applicant mistakenly assumes that the Examiner’s rationale for arriving at the instantly claimed invention must be identical to the Applicant’s rationale (see, e.g., Reply filed 2/01/2024 at page 18 at 1st partial ¶ at “(2)”). This is incorrect. Per MPEP § 2144(IV), the Examiner may rely upon a rationale that differs from the Applicant’s rationale. Third, Kutzko provides and discloses ample art-recognized benefits associated with EDTA usage (e.g., improved purification efficiency, reduced fouling, and improved flow, etc.), which would motivate an artisan to utilize such concentrations as discussed in the rejection above. Therefore, in response to applicant's argument that Kutzko does not additionally teach the same utility of EDTA “on the purified product”, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Here, the use of higher levels of EDTA exactly as suggested in view of the secondary references in order to obtain the benefits disclosed by the secondary reference (e.g., improved purification efficiency, reduced fouling, and improved flow, etc.), would naturally lead to all benefits obtainable from using such higher levels of EDTA. In sum, such arguments are not persuasive.
It is the Examiner’s understanding that the Applicant alleges a lack of reasonable expectation of success (see, e.g., Reply filed 2/01/2024 at page 18-19 at bridging ¶). It is the Examiner’s understanding that Applicant is attempting to allege that there is not a reasonable expectation of successfully obtaining the benefits identified by the Applicant (see id). This does not reflect the applicable US Patent Law because, per MPEP § 2143, a reasonable expectation of success “does not require absolute predictability”, but instead only “at least some degree of predictability” (see, e.g., MPEP § 2143.02(II)), determined not in view of the Applicant’s disclosure, but instead predictability is determined in view of the prior art prior to the filing date (see, e.g., MPEP § 2143.02(III)). Therefore, a reasonable expectation of success is not based upon the Applicant’s reason for arriving at the claimed invention, but rather the “reasonable expectation of success” is based upon the Examiner’s rationales for supporting a determination of obviousness (see also MPEP § 2144(IV)). Here, the Examiner’s rationales for supporting a determination of obviousness are set forth explicitly in the rejection under MPEP § 2143(I)(B), (C), (D), and (F). Therefore, the relevant question concerning predictability, is whether or not the method of the primary reference could have been modified using the higher EDTA levels suggested by the secondary reference to yield a functional method, with “at least some degree of predictability”. Here, as explained in the rejection (but not addressed by the Applicant), there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to utilize known purification methods (e.g., anion-exchange chromatography), with known chemical components (e.g., EDTA), at known concentrations utilized in the prior art (e.g., 20-50 mM), to achieve known and art-recognized benefits (e.g., improved purification efficiency, reduced fouling, and improved flow), in order to purify a known polypeptide of interest (e.g., Factor IX). Accordingly, in the absence of evidence to the contrary, an artisan would reasonably expect such methods as disclosed by the primary reference could successfully and predictably be utilized for the disclosed purpose of purifying Factor IX upon increasing the amount of EDTA utilized to about 20 to 50 mM. Such modifications are well-within the ordinary skill in the art. Critically, Applicant fails to dispute that the prior art is fully enabled for all that it discloses (see, e.g., MPEP §§ 2121(I), 2123(I)-(II)). Applicant fails to explain or address why an artisan would lack a reasonable expectation of success regarding improved purification efficiency, reduced fouling, and improved flow, by simply increasing the EDTA concentration from 10 mM up to about 20 to 50 mM. Applicant fails to provide any credible evidence of inoperability or skepticism of experts supporting an assertion of lack of reasonable expectation of success. Accordingly, in view of the conclusory statements that fail to address the merits of the rejection, and in view of arguments that appear to rely upon an improper interpretation of the MPEP, such arguments are not persuasive.
Examiner notes that Applicant appears to recite conclusory statements (see, e.g., Reply filed 2/01/2024 at § VI at page 15 at final ¶ to page 19 at 1st full ¶), but fails to actually address the merits of the rejection or otherwise address the Examiner’s rationales supporting a determination of obviousness under MPEP § 2143(I)(B), (C), (D), and (F). For example, Applicant fails to dispute that the secondary reference teaches an overlapping range of EDTA, and provides guidance identifying numerous benefits associated with utilizing EDTA in purification processes at those concentration ranges (see, e.g., Rejection above). Accordingly, such arguments are not persuasive because they fail to address the merits of the rejection.
Accordingly, the rejection is maintained.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US 5,136,026 (Aug. 4, 1992; Romisch et al.; cited in IDS filed 10/25/2019 as cite no: 3) was discussed at length in the prior Action, which is incorporated herein (see, e.g., Non-Final mailed 12/15/2020 at pages 46-47). In brief, Romisch discloses that it was found, “surprisingly, that toxic substances can be removed from these proteins by ion exchange chromatography in the presence of chelating reagents in combination with ionic detergents” (see, e.g., US’026 at col 1 lines 44-50). Romisch discloses a method of purifying protein solutions using anion exchange chromatography (id. at claim 1), wherein a chelating agent of “EDTA, EGTA, a salt of citric acid or oxalic acid or a combination thereof” (id. at claim 3 ) is used at a “concentration of 1-100 mmol/l” (id. at claim 4) in an aqueous buffer solution in order to remove toxins (id. at claim 1), and reduces to practice examples wherein EDTA is added at 10 mM to the loading and/or equilibration buffer (see, e.g., Romisch at col 3 line 60 to col 4 line 60, disclosing Examples 1-2 and Table 1, showing that the protein of interest is increased in purity multiple fold following purification).
US 5,061,815 (Oct. 29, 1991; Leu et al.; cited in IDS filed 10/25/2019 as cite no. 1) establishes and evidences that polylysine inherently has the ability to form metal complexes (see, e.g., Leu at claim 1, abs, col 2 lines 26-33).
US 2004/0171103 A1 (Sep. 2, 2004; Bradley et al.; cited in IDS filed 10/25/2019(6 pages) as cite no. 1) was discussed at length in a prior Action, and that discussion is incorporated herein (see, e.g., Non-Final mailed 12/15/2020 at pages 47-48). Examiner notes that the teachings of US’103 have been discussed more extensively in the parent Application (see, e.g., US Application No. 14/813,461 at Non-Final mailed 12/2/2016 at pages 24-25), and those discussions are incorporated herein.
Bonner (Protein Purification, Taylor & Francis Group, 201 pages, ISBN 978-0-415-38511-4 (June 2007); hereafter "Bonner"; cited in IDS filed 10/25/2019 (6 page) as cite no: 7) was discussed at length in a prior Action, and that discussion is incorporated herein (see, e.g., Non-Final mailed 12/15/2020 at pages 48-49).
US 5,641,887 (Jun. 24, 1997; Beckman et al.; cited in previous action), establishes the level of ordinary skill in the prior art regarding chelating agents (see, e.g., '887 at col 4 at line 50 to col 5 at line 4, entitled "Identification of Chelating Functional Groups"). Notably, it was well-within the ordinary skill in the art at the time of the invention to identify equivalent art-recognized chelating agents.
US 4,981,952 (Yan; Jan. 1, 1991; cited in previous action) pertains to and discloses embodiments wherein vitamin K-dependent proteins are purified using anion exchange chromatography (see, e.g., US’952 at title, abs, claims).
Conclusion
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 extension fee 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.
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/RANDALL L BEANE/Primary Examiner, Art Unit 1654
1 See, e.g., Novozymes A/S v. DuPont Nutrition Biosciences APS, 723 F.3d 1336, 1349, 107 U.S.P.Q.2d 1457, 1467, 2013 BL 192990, 14 (Fed. Cir. 2013), explaining that the written description analysis requires “[t]aking each claim . . . as an integrated whole rather than as a collection of independent limitations”.
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