DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination
A request for continued examination under 37 CFR 1.114 was filed in this application after a decision by the Patent Trial and Appeal Board, but before the filing of a Notice of Appeal to the Court of Appeals for the Federal Circuit or the commencement of a civil action. Since this application is eligible for continued examination under 37 CFR 1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the appeal has been withdrawn pursuant to 37 CFR 1.114 and prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant’s submission filed on 3/20/2026 has been entered.
Res Judicata
This instant Application is subject to the Decision of Appeal 2025-002441. Per MPEP § 2190, a patent owner or applicant may be precluded from seeking a claim that is not patentably distinct from a claim that was finally refused or canceled during an administrative trial or federal court proceeding under the doctrine of res judicata.
Claim Status
Claims 61-67, 69-84, 89-95, and 105-118 are pending. Claims 61 and 117 were amended; claims 85-88 and 119 were canceled; and no claims were added in the Reply filed 3/20/2026. Claims 71-76, 80-82, 84-89, 91-95, 108, 110-111, 114, 117-118 remain withdrawn. Claims 61-67, 69-70, 77-79, 83, 90, 105-107, 109, 112-113, and 115-116 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 3/20/2026 raise the issue of new matter and have necessitated a denial of priority. Accordingly, the originally elected species has examined again with respect to prior art within the intervening years of Dec. 18, 2009, to June 28, 2019 (see Denial of Priority, below), and subsequently deemed obvious and/or anticipated by the prior art.
The originally elected species of Example 1, Example 1b, and Table 1 of the original disclosure, 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,1 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 CaCl22, 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, and Applicant failed to identify the claims encompassing the originally 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, 77-79, 83, 90, 105-107, 109, 112-113, and 115-116 as filed 03/20/2026. 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.
In view of 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, 117-118 remain 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 having the ability to complex metal ions;
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 washing fluid comprises a buffered solution that comprises a salt of less than 200 mM and has a pH of 5.5 or lower.
Accordingly, following the PTAB decision of Appeal 2025-002441, Applicant has broadened the claim with respect to the “chemical compounds” encompassed by the claim (previously limited to EDTA and EGTA, but now encompasses any structure “having the ability to complex metal ions”), but narrowed the scope of the claim with respect to the “washing fluid”.
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 X, Facor IX, Factor VIII, Factor II, and activated polypeptide C are each a type of “vitamin K-dependent” polypeptide (see, e.g., Spec. filed 6/28/2019 at 5-6 at bridging ¶, 33 at lines 29-31; see also, instant claims 107, 109, and 112).
The genus of “chemical compound[s] having the ability to complex metal ions” is a functionally defined genus that encompasses at least EDTA, EGTA, and all 48 compounds identified and enumerated previously on record (see, e.g., Action mailed 12/15/2020 at 8-9 at bridging ¶). The genus is not limited by molecular weight3. No consensus structure corresponding to the “ability to complex metal ions” has been identified on record. Therefore, the claim scope is presumably infinitely broad. The phrase is understood to be satisfied by at least compounds in the art taught as capable of binding to complex metal ions.
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. No support for the range of “15 mM to 200 mM” for all possible “chemical compound[s] having the ability to complex metal ions” was identified in the Reply filed 3/20/2026.
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 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 ¶).
Contingent Limitation: In the Reply filed 3/20/2026, Claim 61 was amended to include the following limitation
wherein the washing fluid comprises a buffered solution that comprises a salt of less than 200 mM and has a pH of 5.5 or lower.
The term “washing fluid” has antecedent basis in the claim at the optional step of
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
Per MPEP § 2111.04(II), “[t]he broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met”. Accordingly, the newly added limitation lacks antecedent basis (claim 61 refers to “one or more washing fluids”), but is understood to be a contingent limitation that only applies if claim 61(c) is at issue.
In the Reply filed 3/20/2026, Claim 61 was amended to include the following limitation
wherein washing fluid comprises a buffered solution that comprises a salt of less than 200 mM and has a pH of 5.5 or lower.
This phrase is absent from the originally filed disclosure (see Denial of Priority and New matter rejections, below). The phrase “comprises” is open-ended, and “a salt” is understood to be singular. This is pertinent because the “wherein” clause does not preclude the presence of salt(s) over 200 mM, so long as at least one salt is present at “less than 200 mM”.
Additional claim interpretations are provided below.
Denial of Priority4
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 EP’707, App’740, App’461, or any priority document and therefore the claims lack literal support in these priority documents. The disclosures of EP’707, App’740 and App’461 are representative of the disclosures of the priority documents.
Specifically, the disclosures of EP’707, App’740, and App461 each fail to literally teach or disclose the use of 15 mM to 200 mM of all possible “chemical compound[s] having the ability to complex metal ions” as now claimed and recited at amended claim 61.
In addition, the disclosures of EP’707, App’740, and App461 each fail to literally teach or disclose the limitation reciting and requiring
wherein the washing fluid comprises a buffered solution that comprises a salt of less than 200 mM and has a pH of 5.5 or lower.
The limitation is literally absent from all priority documents, and the ranges of “less than 200 mM” (i.e., 0 mM to 199.99 mM) and “pH 5.5 or lower” (i.e., a pH of 0.0001 to 5.5) are not literally taught on record.
Accordingly, each of EP’707, 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 has found no disclosure pertaining to the usage of all possible “chemical compounds having the ability to complex metal ions” at the specific range of 15 mM to 200 mM as presently claimed has been identified in EP’707, App’740 and App’461. The closest supporting disclosure pertains only to EDTA, but no guidance to extend EDTA-specific ranges to all other possible “chemical compounds having the ability to complex metal ions” appears in any priority document. Furthermore, the newly added “wherein” clause reciting and requiring
wherein the washing fluid comprises a buffered solution that comprises a salt of less than 200 mM and has a pH of 5.5 or lower.
is not supported by implicit or inherent support in any priority document, and the ranges of “less than 200 mM” (i.e., 0 mM to 199.99 mM) and “pH 5.5 or lower” (i.e., a pH of 0.0001 to 5.5) are not supported by any implicit or inherent disclosure within any priority document.
Accordingly, EP’707, 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 all priority documents of record, including 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.
Claim Objections
Claim 113 is objected to because of the following informalities:
Claim 113 is missing the word “is” in the statement “the Vitamin K-dependent polypeptide Factor IXa”.
Appropriate correction is required.
New, Reinstated, Maintained, and/or Revised Rejections
Claim Rejections - 35 USC § 112(b)
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 61-67, 69-70, 77-79, 83, 90, 105-107, 109, 112-113, and 115-116 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.
Amended claim 61 recites and refers to “adding one or more washing fluids comprising the chemical compound” (see claim 61(c)), and subsequently refers to “the washing fluid”, and
wherein the washing fluid comprises a buffered solution that comprises a salt of less than 200 mM and has a pH of 5.5 or lower.
The term “the washing fluid” therefore lacks antecedent basis; it is unclear if the “wherein” clause applies to all of the “one or more washing fluids” potentially present (e.g., if three washing fluids are used, all must each individually satisfy the “wherein” clause limitations), or if the “wherein” clause applies to only one of the “one or more washing fluids” present (i.e., if three washing fluids are used, only one must satisfy the “wherein” clause limitations). Accordingly, the metes and bounds of the claim scope are unclear.
Amended claim 61 recites
wherein the washing fluid comprises a buffered solution that comprises a salt of less than 200 mM and has a pH of 5.5 or lower.
The phrase “a salt of less than 200 mM” is not defined or described in the originally filed disclosure but raises a substantial and material question, namely it is unclear if the phrase refers to a total “salt concentration”, wherein all salts are considered in the aggregate or whether the phrase merely refers to a single salt. To illustrate this issue, it is unclear if the limitation excludes a washing fluid comprising 199 mM of NaCl and 10 mM CaCl2, or not? The total “salt concentration” is over 200 mM, but no single salt is actually present at over 200 mM. To further illustrate this point, would a wash buffer comprising 220 mM sodium chloride and 20 mM Tris satisfy the newly added “wherein” clause or not? Tris would act as a salt and be present at under 200 mM, but NaCl is present over 200 mM. This is pertinent because close prior art exists on record that teaches and claims methods of utilizing a washing buffer “which has a salt concentration of more than 200 mM” (see, e.g., US2008/0207879 at claim 1, ¶¶[0040], [0062]), but wherein the reference explains that such wash buffers may contain various salts at once, and wherein “[i]f salts with polyvalent anions are used (e.g., sulfate or phosphate), the salt concentration should be respectively lower….[t]he more ions, especially anions, are already present in the buffer, the less salt is needed” (see, e.g., US2008/0207879 at ¶[0040]). Therefore, any distinguishing limitations turn upon nuanced interpretations of the metes and bounds of the newly added “wherein” clause at instant claim 61. Accordingly, claim 61 is rejected as indefinite because the metes and bounds of the newly added “wherein” clause are unknown. For purposes of applying prior art, because the phrase “comprises” is open-ended and the added “wherein” clauses literally recites “a salt”, the “wherein” clause does not preclude the presence of salt(s) over 200 mM, so long as at least one salt is present at “less than 200 mM”.
Amended claim 61 recites the contingent limitation at claim 61(c) (i.e., “and/or (c)”, wherein “or” indicates (c) is not required, wherein claim 61(c) pertains to a “washing fluid”), but now recites
wherein the washing fluid comprises a buffered solution that comprises a salt of less than 200 mM and has a pH of 5.5 or lower.
It is unclear if the newly added “wherein” clause further limits only the contingent limitation, or if the contingent clause is intended to further limit all possible “washing fluids” utilized in any embodiment (i.e., embodiments wherein the contingent limitations at claim 61(a) and/or (b) are utilized, but the contingent limitation of claim 61(c) is not practiced), or if the newly added “wherein” clause only applies when the contingent limitation at claim 61(c) is applied. This is relevant because it substantially and materially alters the pending claim scope, and close prior art exists and has been applied on record. Specifically, if the “wherein” clause is applicable to all possible “washing fluids” regardless of whether or not the contingent limitation at claim 61(c) is utilized, then the amended claim scope excludes the prior rejection of record in view of 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), which was affirmed in the Decision of Appeal 2025-002441. However, if the “wherein” clause only limits embodiments that require the contingent limitation at claim 61(c), then the newly added “wherein clause” does not exclude the prior rejection since it the rejection is premised upon increasing the EDTA in the loading fluid and equilibration fluid (i.e., instant claim 61(a) and 61(b), but not the contingent limitation at claim 61(c)) (see, e.g., Final mailed 3/01/2024 at 32 at final ¶5, wherein the rejection was affirmed in the Decision of Appeal 2025-002441). Accordingly, the proper interpretation of the “wherein” clause materially and substantially impacts the metes and bounds of amended claim 61, and therefore renders the claim scope indefinite. For purposes of applying prior art, the newly added “wherein” clause explicitly recites “washing fluid”, and therefore the “wherein” clause is reasonably understood to refer back to and further limit only the contingent limitation of claim 61(c). Per MPEP § 2111.04(II), “[t]he broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met”. Accordingly, the “wherein” clause is understood to apply only if the contingent limitation at claim 61(c) is evoked.
Claim 61 attempts to define a subgenus of chemical compounds having unknown structural metes and bounds by reciting a functional limitation that the desired chemical compounds are supposed to achieve, namely claim 61 recites “a chemical compound having the ability to complex metal ions”, but the functional limitation “having the ability to complex metal ions” fails to correspond to a clear structure/function relationship of record, commensurate in scope with the claims. Per MPEP § 2173.05(g),
[T]he use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite. In re Swinehart, 439 F.2d 210, 213 (CCPA 1971). For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. . .
Here, the claims merely recite a description of functions or results to be achieved by the invention rather than a description of the structures actually capable of achieving the desired functions, and therefore the claims are indefinite per MPEP § 2173.05(g). This is reasonable because MPEP § 2173 identifies that the primary purpose of the requirement is to inform the public of the boundaries of what constitutes infringement of the patent, but here it is unclear what compounds do or do not infringe upon the scope of claim 61, which presumably reads upon aptameric nucleotides, polypeptides, small molecules, chelators, enzymes, etc. Notably, no minimal Kd value is recited and no minimal binding conditions (i.e., solvents, salt concentrations, etc.) are recited, meaning that the scope of “chemical compounds” may encompass millions of species of chemical compounds lacking any common chemical moieties. Although it is reasonably assumed that the limitations of claim 61 may be fully satisfied by EDTA and EGTA, zero additional guidance or structure/function teachings are presented identifying the metes and bounds of chemical compounds that do or do not satisfy the functional limitation recited at amended claim 1. Notably, the courts have stated that
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
Accordingly, because it is unclear what compounds do or do not satisfy the functional limitation of claim 61, an artisan would be unable to identify infringing from non-infringing compounds. Accordingly, claim 61 is rejected as indefinite. For purposes of applying prior art, claim 61 is understood to read upon at least the chemical compounds of EDTA and EGTA.
Claims 62-67, 69-70, 77-79, 83, 90, 105-107, 109, 112-113, and 115-116 depend directly or indirectly from an indefinite base claim, and do not clarify the indefiniteness of the base claim. Accordingly, these claims are rejected for the reasons applicable to claim 61 as set forth above.
Claims 61-67, 69-70, 77-79, 83, 90, 105-107, 109, 112-113, and 115-116 are rejected.
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, and 115-116 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. Claim 61 was amended in the Reply filed 3/20/2026 and broadened with respect to the “chemical compounds” claimed, but narrowed with respect to the contingent limitation at claim 61(c).
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 and all other possible “chemical compounds having the ability to complex metal ions” is not literally taught or disclosed in the originally filed disclosure. In addition, the ranges and limitation regarding a “washing fluid” reciting and requiring
wherein the washing fluid comprises a buffered solution that comprises a salt of less than 200 mM and has a pH of 5.5 or lower
is literally absent from the originally filed disclosure, and the ranges of “a salt of less than 200 mM” (i.e., 0.000 nM to 199.99 mM) and “pH 5.5 or lower” (i.e., a pH of ~0.00001 to 5.5) are not literally taught on record.
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 of 15-200 mM for a “chemical compound” 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 all other “chemical compounds”. Accordingly, there is no implicit or inherent support for the instant claim scope.
In addition, upon review the Examiner has found no literal, inherent, or implicit support for the newly added limitation regarding a “washing fluid”:
wherein the washing fluid comprises a buffered solution that comprises a salt of less than 200 mM and has a pH of 5.5 or lower.
This “wherein” clause and the recited limitations and ranges appear absent from the originally filed disclosure because the ranges of “a salt of less than 200 mM” (i.e., 0 mM to 199.99 mM) and “pH 5.5 or lower” (i.e., a pH of 0.0001 to 5.5) are not literally, inherently, or implicitly taught on record.
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 3/20/2026, Applicant directed Examiner to two passages (see, e.g., Reply filed 3/20/2026 at Remarks at 1st full ¶, directing the Examiner to the as-filed specification at page 22 at line 29 to page 23 at line 3, and page 51 at line 28 to page 52 at line 5). These passages have been reviewed, but fail to provide literal, implicit, or inherent disclosures commensurate in scope with the claimed invention or otherwise the limitations and ranges recited therein. No support for the claim scope as an integrated whole6 was identified. 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, or other “chemical compound” besides EDTA. 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 or other chemical compounds.
At best, Applicant may be attempting to allege that such disclosures pertaining to EDTA and other ranges of pH and salt concentration render the claimed ranges “obvious” (see, e.g., Reply filed 3/20/2026 at Remarks at 1st full ¶). 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; 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"). 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)).
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, and 115-116 are rejected.
Claim Rejections - 35 USC § 1027
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, and 115-116 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, 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, and 115-116, and all claims reading upon the originally elected species are rejected as anticipated by the prior art.
Claims 61-63, 65, 69-70, 77-79, 90, 105-107, 109, 112, and 115-116 are rejected under pre-AIA 35 U.S.C. 102(b) as being anticipated by US2008/0207879 A1 (Artur et al.; Aug. 28, 2008; cited in previous action) as evidenced by Fischer et al.8.
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. Amended claim 61 has been rejected as indefinite under 35 USC § 112(b) as explained above; for purposes of the instant rejection, unless stated to the contrary, the newly added “wherein” clause is understood to further limit the contingent limitation of claim 61(c), but not the general claim scope or the contingent limitations of claims 61(a) and/or 61(b). Additional claim interpretations are set forth below.
Regarding the “chemical compound having the ability to complex metal ions”, Fischer evidences that Tris is known in the prior art as a chemical compound capable of complexing metal ions (see, e.g., Fischer at abs, Table 1-2 at page 526, Table 3 at 527, Table 4 at 528, Fig. 3 on 528). Accordingly, Tris is an art-recognized “chemical compound capable of complexing metal ions”.
Regarding instant claims 61-63, 65, 69-70, 77-79, 90, 105-107, 109, 112, and 115-116, 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 61-65). 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 20 mM Tris (see, e.g., US’879 at ¶¶[0137]-[0139], Tables VII-VIII) and a loading buffer containing 20 mM Tris (see, e.g., US’879 at ¶[0137], Tables VII-VIII, noting that the cell culture supernatant was diluted with “dilution buffer” and 10 mM EDTA, prior to loading, wherein the “dilution buffer” comprised 20 mM Tris). Accordingly, the equilibration and loading buffers each contain 20 mM Tris (see, e.g., US’879 at ¶¶[0137]-[0139], Tables VII-VIII; compare id. with instant claims 61-65, 69-70, and 105-106). 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, at US’879 at Example 5 at ¶¶[0137]-[0139], Tables VII-VIII). Regarding instant claims 61-62 and steps (a) and (b), at Example 5 of US’879, the equilibration and loading buffers each comprise 20 mM Tris (see, e.g., US’879 at ¶¶[0137]-[0139], Tables VII-VIII; compare id. with instant claims 61-63 and 65). 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, loading buffer, and claims 61(a), 61(b), 62-63, 65, 69-70, 77-79, and 105-106, 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). US’879 discloses that the loading buffer contained 20 mM Tris and had a pH of 7.4(see, e.g., US’879 at ¶[0137], Tables VII-VIII, noting that the cell culture supernatant was diluted with “dilution buffer” and 10 mM EDTA, prior to loading, wherein the “dilution buffer” comprised 20 mM Tris). 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). 9Regarding 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, the 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 elution “Gradient” buffer B contains NaCl).
Accordingly, claims 61-63, 65, 69-70, 77-79, 90, 105-107, 109, 112, and 115-116 are rejected in view of US’879 wherein Tris is understood to be a chemical compound “having the ability to complex metal ions”.
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, 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. This rejection is revised from the Final mailed 3/01/2024 as affirmed in the Decision of Appeal 2025-002441 and addresses the situation wherein the “chemical compound” is limited to EDTA10. Amended claim 61 has been rejected as indefinite under 35 USC 112(b) as explained above; for purposes of the instant rejection, unless stated to the contrary, the newly added “wherein” clause is understood to further limit the contingent limitation of claim 61(c), but not the general claim scope or the contingent limitations of claims 61(a) and/or 61(b). Additional claim interpretations are set forth below.
Regarding instant claims 61-62, 77-79, 90, 107, 109, 112, and 115-116, 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). 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 and loading buffer that each contain 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). 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). 11Regarding 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, the 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 elution “Gradient” buffer B contains NaCl).
The prior art of US’879 differs from the instant claims as follows12: 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 claim 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 (instant claim 61(b)) or the equilibration fluid (instant claim 61(a)) 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.
Regarding the amended claim 61(c) and the “wherein” clause reciting “wherein the washing fluid comprises a buffered solution that comprises a salt of less than 200 mM and has a pH of 5.5 or lower”, claim 61 has been rejected as indefinite under 35 USC §112(b), and those discussions are incorporated herein. The “wherein” clause literally refers to “washing fluid”, which appears only in the contingent limitation of claim 61(c), and is therefore understood to further limit only embodiments that require invoking the contingent limitation of claim 61(c). Per MPEP § 2111.04(II), “[t]he broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met”. Accordingly, the “wherein” clause pertaining to the washing fluid is understood to apply only if the contingent limitation at claim 61(c) is evoked. However, the instant rejection pertains to claimed embodiments having EDTA at 20 to 50 mM in loading fluids and equilibration fluids, but not washing fluids, and therefore the contingent limitation regarding washing fluids is not required.
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 (i.e., within loading and/or equilibration fluids) 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, 90, 107, 109, 112, and 115-116 are obvious in view of the prior art.
Response to Arguments
Applicant's arguments filed 3/20/2026 have been fully considered but they are not persuasive (see, e.g., Reply filed 3/20/2026 at 9 at § Remarks). Applicant does not dispute the Decision of Appeal 2025-002441. Applicant does not dispute any rejections set forth in the Final mailed 3/01/2024 with specificity, but instead requests that the Office “consider this Amendment” (see, e.g., Reply filed 3/20/2026 at 9 at § Remarks). The amendment has been considered but does not overcome the rejections and issues of record.
The Examiner’s position as set forth in the Final mailed 3/01/2024 and Examiner’s Answer to Appeal Brief mailed 3/05/2025, remain pertinent and are incorporated herein.
Accordingly, all arguments raised in the response filed 3/20/2026 have been fully considered but not found persuasive as explained above. No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RANDALL L BEANE whose telephone number is (571)270-3457. The examiner can normally be reached Mon.-Fri., 7 AM to 2 PM ET.
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/RANDALL L BEANE/Primary Examiner, Art Unit 1654
1 Note that MES, NaCL and disodium-EDTA each act as a salt. Therefore, the total salt concentration is 200 mM.
2 Note that MES, NaCl, and CaCl2 each act as salts. Therefore, the total salt concentration is >200 mM.
3 In the parent Application, Applicant identified that the genus of “‘chemical compounds’ can include molecules above a molecular weight of 1000 Da” (see, e.g., Reply filed 11/17/2014 in US 13/516,740 at 16-17 at bridging ¶). See 37 CFR 1.56(b)(1)-(3); see also Teva Pharmaceuticals USA, Inc. v. Sandoz, Inc., 789 F. 3d 1335 (2015), at 1343, stating “We have said before, and reaffirm today, that past and future prosecution of related patents may be relevant to the construction of a given claim term”. See, also, Springs Window Fashions LP v. Novo Indus., L.P., 323 F.3d 989, 995 (Fed.Cir.2003), noting that “The public notice function of a patent and its prosecution history requires that a patentee be held to what he declares during the prosecution of his patent”.
4 The Denial of Priority is revised and reinstated in view of Applicant’s amendments broadening the pending claim scope as filed 3/20/2026 (see Final mailed 3/01/2024).
5 Stating that “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” (see, e.g., Final mailed 3/01/2024 at 32 at final ¶, wherein the rejection was affirmed in the Decision of Appeal 2025-002441).
6 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”.
7 The rejection over WO’235 is reinstated in view of the new Denial of Priority, above. The denial of priority was necessitated by the amendments filed 3/20/2026. Accordingly, WO’235 is applicable prior art.
8Fischer et al., Metal Ion/Buffer Interactions, Eur. J. Biochem., vol. 94:523-530 (1979); cited in Action mailed 12/15/2020).
9 In view of the amendments filed 3/20/2026, Claim 83 is understood to now require the contingent step of claim 61(c). Therefore, although 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), this buffer does not satisfy the pH range recited for the “washing fluid” present in the contingent limitation of claim 61(c).
10 In view of the broadening of the scope of claim 61 as filed 3/20/2026, US’879 has also been applied under 35 USC 102 above, with respect to a different metal-binding chemical compound, namely Tris. However, the 103 rejection maintained/revised above pertains to the narrower scope previously examined, wherein the chemical compound is EDTA.
11 In view of the amendments filed 3/20/2026, Claim 83 is understood to now require the contingent step of claim 61(c). Therefore, although 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), this buffer does not satisfy the pH range recited for the “washing fluid” present in the contingent limitation of claim 61(c).
12 In view of the broadening of the scope of claim 61, US’879 has been applied under 35 USC 102 above, with respect to a different metal-binding chemical compound. The 103 rejection pertains to the narrower scope previously examined, wherein the chemical compound is EDTA.
Prosecution Insights