DETAILED ACTION
Status of the Application
Claims 1-3, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36, 38 are pending.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
An amendment of claims 1-2, 6-9, 14, 21, 28 and cancellation of claim 37 as submitted in a communication filed on 8/19/2026 is acknowledged.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8/19/2026 has been entered.
Claims 1-3, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36, 38 are at issue and are being examined herein.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 8/19/2026 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
Claim 36 is 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 pre-AIA the applicant regards as the invention.
Claim 36 is indefinite in the recitation of “SFM4CHO” for the following reasons. As set forth in MPEP § 2173.05(u), if a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of the 35 USC § 112(b) or pre-AIA 35 USC § 112, second paragraph. Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used to properly identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. In fact, the value of a trademark would be lost to the extent that it became descriptive of a product, rather than used as an identification of a source or origin of a product. The use of a trademark or a trade name in a claim to identify or describe a material or product would not only render a claim indefinite, but would also constitute an improper use of the trademark or trade name. Correction is required.
When amending the claims, applicant is advised to carefully review all examined claims and make the necessary changes to ensure proper antecedent basis and dependency.
Claim Rejections - 35 USC § 112(a) or First Paragraph (pre-AIA )
Claims 1-3, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36 remain 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 claim(s) contains 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.
This rejection has been discussed at length in the prior Office action. It is maintained for the reasons of record and those set forth below.
Applicant argues that the present claims are directed to a method of producing a recombinant alkaline phosphatase and that the claimed method does not purport to claim a genus of polypeptides. Applicant states that the claims define the relevant polypeptides by specific structure and do not seek to claim an undefined genus solely by reference to a desired biological activity. Applicant states that the proper inquiry is whether the specification reasonably conveys to a person of ordinary skill in the art that the inventors were in possession of the claimed method using polypeptides falling within the claimed sequence identity range. Applicant states that asfotase alfa is a well characterized polypeptide that includes the soluble portion of a tissue nonspecific alkaline phosphatase, an Fc region, and a polyaspartate bone targeting moiety. Applicant cites WO 2011/134084 in support of the argument that variants of this polypeptide have been generated and characterized. Applicant states that the specification discloses variants of alkaline phosphatase polypeptides, Fc regions and negatively charged bone targeting moieties. Applicant states that the skill and knowledge of the art coupled with the disclosure of the specification would allow a skilled person to unambiguously conclude that the present Applicant was in possession of the genus of polypeptides of the present claims.
Applicant’s arguments have been fully considered but not deemed persuasive to overcome the instant rejection. The Examiner acknowledges the teachings of the specification and the prior art. However, the Examiner disagrees with Applicant’s contention that the entire scope of the claims is adequately described.
With regard to the argument that the present claims are directed to a method of producing a recombinant alkaline phosphatase and that the claimed method does not purport to claim a genus of polypeptides, it is noted that while it is agreed that the claims are directed to a method and not to a genus of polypeptides, the method of the claims require the production of a genus of recombinant alkaline phosphatases. Therefore, the genus of alkaline phosphatases recited is essential to practice the claimed invention. In the instant case, one of skill in the art would require to know which structural variants of the polypeptide of SEQ ID NO: 1 having at least 90% sequence identity to the polypeptide of SEQ ID NO: 1 have alkaline phosphatase activity, so that one could transfect cells that can recombinantly produce the recited alkaline phosphatases. As previously indicated, the total number of variants having at least 90% sequence identity to the polypeptide of SEQ ID NO: 1 that result from amino acid substitutions within the polypeptide of SEQ ID NO: 1 is 726!x1973/(726-73)!/73! or 8.31x10194 variants. See calculations previously provided. Neither the specification nor the prior art provide those structural features required in variants having the recited % sequence identity such that the desired alkaline phosphatase activity is observed. No structure/function correlation has been provided that would allow one of skill in the art to determine a priori from an infinite number of structural variants of the polypeptide of SEQ ID NO: 1 having the recited % sequence identity those variants having alkaline phosphatase activity.
With regard to the arguments that (i) asfotase alfa is a well characterized polypeptide that includes the soluble portion of a tissue nonspecific alkaline phosphatase, an Fc region, and a polyaspartate bone targeting moiety, and (ii) the prior art and the specification disclose variants of alkaline phosphatases, it is noted that while it is agreed that the amino acid sequence of asfotase alfa disclosed by Godowat et al. comprises SEQ ID NO: 1 of the instant application, WO 2011/134084 discloses the structure of a limited number of fusion protein that comprise a soluble alkaline phosphatase and Fc domains, and the specification discloses a single recombinant alkaline phosphatase which is a fusion of a soluble alkaline phosphatase and an Fc domain (SEQ ID NO: 1), neither the specification nor the prior art discloses those structural features within the polypeptide of SEQ ID NO: 1 that can be modified and those that should be maintained to obtain a variant having the recited % sequence identity which maintains the desired enzymatic activity. Moreover, neither the specification nor the prior art discloses a structure/function correlation that would allow one of skill in the art to determine from an infinite number of structural variants that have the recited % sequence identity, those that have the desired alkaline phosphatase activity.
Guo et al. (PNAS 101(25):9205-9210, 2004) teach that the percentage of random single substitution mutations which inactivate a protein for the protein 3-methyladenine DNA glycosylase is 34% and that this number appears to be consistent with other studies in other proteins as well. Guo et al. further show in Table 1 that the percentage of active mutants for multiple mutants appears to be exponentially related to this by the simple formula (0.66)N x 100% where N is the number of mutations introduced. In the instant case, for a protein having 90% sequence identity to SEQ ID NO: 1, N is equivalent to 73 (73= 0.1x726; SEQ ID NO: 1=726 amino acids), and (0.66)73 X 100% or 6.7 x 10-12% of random mutants having 90% sequence identity to SEQ ID NO: 1 would be active. In other words, the estimate of Guo et al. predicts that 1 in 1.49x1013 variants having 90% sequence identity to SEQ ID NO: 1 would have activity (1/(0.66)N ). In view of this, one of skill in the art would expect that the vast majority of the species having the recited % sequence identity to the polypeptide of SEQ ID NO: 1 lack enzymatic activity.
As explained in the prior Office action, the art teaches several examples of how even highly structurally homologous polypeptides can have different enzymatic activities. See the teachings of Witkowski et al., Tang et al. and Seffernick et al. previously discussed. Therefore, in the absence of some guidance as to which structural variants of the polypeptide of SEQ ID NO: 1 are more likely to have the desired activity, one cannot reasonably conclude that the skill and knowledge of the art coupled with the disclosure of the specification would allow a skilled person to unambiguously conclude that the present Applicant was in possession of the genus of polypeptides of the present claims. As such, one cannot reasonably conclude that the entire genus of alkaline phosphatases required by the claims are adequately described.
Claims 1-3, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for producing of the protein of SEQ ID NO: 1, does not reasonably provide enablement for a method for producing alkaline phosphatase which is a variant of the polypeptide of SEQ ID NO: 1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
This rejection has been discussed at length in the prior Office action. It is maintained for the reasons of record and those set forth below.
Applicant states that the specification provides considerable guidance for a skilled artisan to practice the claimed production method using alkaline phosphatase variants within the claimed sequence identity range. Applicant is of the opinion that the Office has not provided any evidence or explanation as to why the present claims would not be enabled to their full scope. Applicant states that one of skill in the art would readily recognize that the teachings of the present application with regard to the claimed method could be applied to alkaline phosphatase polypeptides within the scope of the present claims without undue experimentation. Applicant states that the claims are directed to the production of polypeptides having a defined degree of sequence identity and the specification provides guidance regarding alkaline phosphatase domains, Fc regions and negatively charged bone-targeting moieties that may be incorporated into such variants. Applicant states that variants of asfotase alfa and related fusion proteins were known in the art, as evidenced by WO 2011/134084, thus showing that polypeptides failing within the recited % sequence identity range were neither hypothetical nor unpredictable. Applicant submits that given the state of the art, the known structural features of such variants and the guidance provided, a skilled artisan would have been able to select and produce polypeptides within the claimed sequence identity range using routine techniques without undue experimentation. Applicant states that the Office has not presented evidence as to why the recited method steps would not apply to other peptides within the scope of the claims, or why practicing the full scope of the claimed method would require undue experimentation.
Applicant’s arguments have been fully considered but not deemed persuasive to overcome the instant rejection. The Examiner acknowledges the teachings of the prior art as well as the teachings of the specification. However, the Examiner disagrees with Applicant’s contention that the full scope of the claims is enabled by the teachings of the specification.
With regard to the argument that one of skill in the art would readily recognize that the teachings of the present application with regard to the claimed method could be applied to alkaline phosphatase polypeptides within the scope of the present claims without undue experimentation, it is noted that the claims are directed to a method for producing a recombinant alkaline phosphatase, wherein said method requires host cells that can recombinantly produce the genus of alkaline phosphatases recited. As previously stated, in the instant case, one of skill in the art would have to know which structural variants of the polypeptide of SEQ ID NO: 1 having at least 90% sequence identity to the polypeptide of SEQ ID NO: 1 have alkaline phosphatase activity, so that one could transfect cells that can recombinantly produce the recited alkaline phosphatases. The alkaline phosphatases recited are essential to practice the claimed invention. However, it is reiterated herein that neither the specification nor the prior art teach how to envision the structure of those variants of the polypeptide of SEQ ID NO: 1 that have the recited % sequence identity and also have the desired alkaline phosphatase activity.
With regard to the argument that the claims are directed to the production of polypeptides having a defined degree of sequence identity and the specification provides guidance regarding alkaline phosphatase domains, Fc regions and negatively charged bone-targeting moieties that may be incorporated into such variants, it is noted that while the number of structural variants of the polypeptide of SEQ ID NO: 1 that have at least 90% sequence identity to the polypeptide of SEQ ID NO: 1 is essentially infinite, the specification and the prior art are silent with regard to the structural features required in any variant of the polypeptide of SEQ ID NO: 1 having the recited % sequence identity such that the variant has the desired activity. See calculations provided in the prior Office action where it is shown that the number of structural variants having the recited % sequence identity is essentially infinite. No structure/function correlation has been provided to determine which structural variants having the recited % sequence identity have alkaline phosphatase activity. Therefore, one of skill in the art would have to test an infinite number of variants to find those that have alkaline phosphatase activity to practice the claimed invention.
With regard to the argument that variants of asfotase alfa and related fusion proteins were known in the art, as evidenced by WO 2011/134084, thus showing that polypeptides failing within the recited % sequence identity range were neither hypothetical nor unpredictable, it is reiterated herein that while it is agreed that the amino acid sequence of asfotase alfa disclosed by Godowat et al. comprises SEQ ID NO: 1 of the instant application, and that WO 2011/134084 discloses the structure of a limited number of fusion protein that comprise a soluble alkaline phosphatase and Fc domains, neither the specification nor the prior art discloses those structural features within the polypeptide of SEQ ID NO: 1 that can be modified and those that should be maintained to obtain a variant having the recited % sequence identity which maintains the desired enzymatic activity. Moreover, the prior art teaches that (a) determining function based solely on structural homology, and (b) modification of a protein’s amino acid sequence to obtain the desired activity without any guidance /knowledge as to which amino acids in a protein are tolerant of modification which ones are conserved are highly unpredictable. See the teachings of Singh et al., Sadowski et al., Witkowski et al., Tang et al. and Seffernick et al. previously discussed.
With regard to the argument that given the state of the art, the known structural features of such variants and the guidance provided, a skilled artisan would have been able to select and produce polypeptides within the claimed sequence identity range using routine techniques without undue experimentation, it is noted that while it is agreed that methods to create variants having the recited % sequence identity and enzymatic assays were known in the prior art, the issue in the instant case is that in view of the lack of information as to which structural variants of the polypeptide of SEQ ID NO: 1 are more likely to have alkaline phosphatase activity, one of skill in the art would have to test an essentially infinite number of variants to find those with the desired activity. As previously indicated, the teachings of Guo et al. suggest that the vast majority of structural variants of the polypeptide of SEQ ID NO: 1 are not expected to have alkaline phosphatase activity. The estimate of Guo et al. predicts that 1 in 1.49x1013 variants having 90% sequence identity to SEQ ID NO: 1 would have activity. Since there is an immense number of mutants that one of skill in the art would have to test to find one enzymatically active variant, one of skill in the art cannot possibly conclude that the amount of experimentation required with current techniques (i.e., high throughput mutagenesis and screening techniques) in the art is routine. While enablement is not precluded by the necessity for routine screening, if a large amount of screening is required, the specification must provide a reasonable amount of guidance with respect to the direction in which the experimentation should proceed. Such guidance has not been provided in the instant specification.
With regard to the argument that the Office has not presented evidence as to why the recited method steps would not apply to other peptides within the scope of the claims, it is reiterated herein that the method claimed requires the step of culturing a host cell able to produce a genus of recombinant alkaline phosphatases having at least 90% sequence identity to the polypeptide. Therefore, one of skill in the art would have to know which structural variants of the polypeptide of SEQ ID NO: 1 having at least 90% sequence identity to the polypeptide of SEQ ID NO: 1, from an infinite number of variants that meet the recited % sequence identity, have alkaline phosphatase activity, so that one could transfect host cells that can recombinantly produce the recited alkaline phosphatases.
With regard to the argument that the Office has not presented evidence as to why practicing the full scope of the claimed method would require undue experimentation, it is reiterated herein that the number of structural variants that meet the recited % sequence identity is essentially infinite. Neither the specification nor the prior art provide those structural features required in variants having the recited % sequence identity such that the desired alkaline phosphatase activity is observed. No structure/function correlation has been provided that would allow one of skill in the art to determine from an infinite number of structural variants of the polypeptide of SEQ ID NO: 1 having the recited % sequence identity those variants having alkaline phosphatase activity. While it is agreed that methods of generating variants of a polypeptide and enzymatic assays were known in the art at the time of the invention, it was not routine in the art to screen by a trial and error process for an essentially infinite number of proteins to find a protein with alkaline phosphatase activity. In the absence of (i) a rational and predictable scheme for selecting those proteins most likely to have the desired functional features, and/or (ii) a correlation between structure and activity, one of skill in the art would have to test an essentially infinite number of proteins to determine which ones have the desired functional characteristics. Therefore, for the reasons of record and those set forth above, one of skill in the art cannot reasonably conclude that the entire scope of the claims is fully enabled by the teachings of the specification and/or the prior art.
Claim Rejections - 35 USC § 102 (AIA )
Claims 1-3, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36-38 were rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Godawat et al. (WO 2019/190752 published 10/3/2019; cited in the IDS). In view of the amendment of claim 1, which now requires taking an aliquot at day 6 to 8 after inoculation, and subjecting the aqueous culture medium to a filtration step to obtain a bulk drug solution (BDS), wherein the filtration step has a duration of less than 9 hours if the TSAC concentration of the aliquot is less than 2.5 mol/mol, wherein the filtration step has a duration of 10-14 hours if the TSAC concentration of the aliquot is 2.5-2.7 mol/mol, wherein the filtration step has a duration of 23-27 hours if the TSAC concentration of the aliquot is 2.8-3.0 mol/mol, or wherein the filtration step has a duration of 38-42 hours if the TSAC concentration of the aliquot is greater than 3.0 mol/mol, this rejection is hereby withdrawn.
Claim Rejections - 35 USC § 103 (AIA )
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 5-9, 14, 16, 18, 21, 24, 26, 28, 29, 31, 36, 38 are rejected under 35 U.S.C. 103 as being unpatentable over Godawat et al. (WO 2019/190752 published 10/3/2019; cited in the IDS).
Godawat et al. a method for the production of an alkaline phosphatase (e.g., asfotase alfa) by inoculating a cell culture medium with CHO cells that express said alkaline phosphatase, and harvesting the cell culture medium after the desired cell density has been reached (pages 49-50, Example 1, paragraph [0166]). Godawat et al. teach that asfotase alfa is fusion glycoprotein that comprises the catalytic domain of a human alkaline phosphatase, an Fc domain, and a deca-aspartate peptide (page 2, paragraph [0005]) and comprises SEQ ID NO: 1 (page 3, paragraph 008]), which is identical to the protein of SEQ ID NO: 1 of the instant application. See alignment below.
Godawat et al. teach measuring TSAC before and after harvest (page 57, Example 4, TSAC Measurement Before and After Harvest). Godawat et al. teach that the cell culture fluid (CCF) samples (before harvest) were taken at the end of the production bioreactor run. Godawat et al. teach harvesting at 200-288 hours (page 38, Harvest) and maintaining a constant temperature for 40-200 hours after inoculation, which is the culturing time (page 31, Temperature). Therefore, Godawat et al. teach measuring TSAC in an aliquot at approximately 8 days (200 hours; end of the production bioreactor run) after inoculation and culturing times that encompass 144-192 hours (6-8 days) after inoculation. Godawat et al. teach that prior studies suggested that delaying harvesting time was associated with viability and TSAC decline (page 38, paragraph [0131]). Godawat et al. teach that during manufacturing, the TSAC content is an important value and is monitored closely and that identification and quantitation of sialic acid in asfotase alfa samples at various stages of manufacture was performed by HPAE-PAD (page 50, paragraph [00168]), including before and after harvest (page 51, Example 2, paragraph [0171]; page 58, Example 5). Godawat et al. teach that Figure 10 shows that TSAC decreases significantly during ultrafiltration (page 58, paragraph [00187]). Godawat et al. teach that a multivariate evaluation of three factors during ultrafiltration (UFDF1) was made using data from harvest samples collected at various hold times (page 58, paragraphs [00187]-[00188]). Godawat et al. teach that the TSAC at Protein A pool was compared to the TSAC value at HCCF for the respective harvest and the total decrease in TSAC from HCCF (TSAC drop) was calculated for each ultrafiltration hold condition. Godawat et al. teach that a JMP model was created using this data and that a prediction profiler is shown in Figure 12. Godawat et al. teaches that the data collected suggests reducing the range of the hold time of the ultrafiltration step to 14-42 hours (page 59, paragraphs [00189]-[00192]). Figure 12 provides the TSAC drop (drop in TSAC before and after filtration) expected for a particular hold time (filtration time). Figure 12 shows that for (i) a TSAC drop of 1 mol/mol, the hold time is approximately 23 hours, (ii) a TSAC drop of 0.7 mol/mol, the hold time is approximately 10 hours, (iii) a TSAC drop of 1.5 mol/mol, the hold time is approximately 40 hours, and (iv) a TSAC drop of less than 0.6 mol/mol, the hold time is approximately 8 hours. Therefore, Figure 12 shows that the larger the hold time, the larger the TSAC drop.
Godawat et al. teach purification of samples taken for TSAC determination with a protein A column (page 58, paragraph [00188]). Godawat et al. teach the use of acid hydrolysis for determination of TSAC (page 39, paragraph [0134]). Godawat et al. teach the harvested culture medium is obtained by centrifugation and filtration to remove solids and cell debris (page 50, paragraph [01666]; page 17, paragraph [0073]). Therefore, it follows that the samples from the harvested culture medium used to determine TSAC have been centrifuged and the supernatant removed prior to TSAC determination. Godawat et al. teach that the harvested culture medium has a TSAC of 2.1 mol/mol to about 4.3 mol/mol (page 41, paragraph [00143]). Godawat et al. teach that the bioreactor can have a volume of 0.25 L to 25000 L (page 62, claims 10-12). Godawat et al. teach that the inoculated medium can be EX-CELL® 302 serum free medium, CD DG44 medium, or SFM4CHO medium (page 62, claim 9). Godawat et al. teach lyophilization of the purified alkaline phosphatase (page 40, paragraph [0139]).
Claims 1-3, 5-9, 14, 16, 18, 21, 24, 26, 28, 29, 31, 36, 38 are directed in part to a method for producing a recombinant alkaline phosphatase, wherein said recombinant alkaline phosphatase has at least 90% sequence identity to the polypeptide of SEQ ID NO: 1, wherein said method comprises inoculating a bioreactor having a volume of at least 2 L to 20000 L which comprises a culture medium that is CD DG44 or SFM4CHO with a CHO cell that expresses the recombinant alkaline phosphatase, obtaining an aqueous culture medium comprising the recombinant alkaline phosphatase, obtaining an aliquot from the aqueous culture medium at day 6 to day 8 after inoculation to determine the total sialic content (TSAC) molar concentration per mole of the recombinant alkaline phosphatase in the aliquot, harvesting the aqueous culture medium, and subjecting the aqueous culture medium to a filtration step to obtain a bulk drug solution (BDS), wherein the filtration step has a duration of less than 9 hours if the TSAC concentration is less than 2.5 mol/mol, wherein the filtration step has a duration of 10-14 hours if the TSAC concentration is 2.5-2.7 mol/mol, wherein the filtration step has a duration of 23-27 hours if the TSAC concentration is 2.8-3.0 mol/mol, wherein the filtration step has a duration of 38-42 hours if the TSAC concentration is greater than 3.0 mol/mol, wherein the filtration step is performed at a temperature of 15 C to 25 C, wherein the determination of TSAC requires acid hydrolysis to release the TSAC, wherein the aliquot is centrifuged and the supernatant removed, wherein the supernatant removed is applied to a Protein A column, wherein the BDS is lyophilized.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to take an aliquot from the aqueous culture medium at day 6 to day 8 after inoculation to determine the total sialic content (TSAC) molar concentration per mole of the recombinant alkaline phosphatase in the aliquot, harvesting the aqueous culture medium earlier, and subjecting the aqueous culture medium to a filtration step to obtain a bulk drug solution (BDS), wherein the filtration step has a duration of less than 9 hours if the TSAC concentration is less than 2.5 mol/mol, wherein the filtration step has a duration of 10-14 hours if the TSAC concentration is 2.5-2.7 mol/mol, wherein the filtration step has a duration of 23-27 hours if the TSAC concentration is 2.8-3.0 mol/mol, wherein the filtration step has a duration of 38-42 hours if the TSAC concentration is greater than 3.0 mol/mol, in the method of Godawat et al. A person of ordinary skill in the art is motivated to take an aliquot from the aqueous culture medium at day 6 to day 8 after inoculation to determine the total sialic content (TSAC) molar concentration per mole of the recombinant alkaline phosphatase in the aliquot, and perform a purification step of the harvested medium for the periods of times recited based on the recited TSAC concentrations of the aliquot because (i) Godawat et al. teach culturing times of 6 -8 days for the production of the alkaline phosphatase and also teach that delaying harvesting was associated with viability and TSAC decline, (ii) Godawat et al. teach measuring the TSAC of the culture prior to harvest, (iii) Godawat et al. provides a prediction tool to estimate the duration of the filtration time for a desired TSAC drop after harvest, and (iv) the filtration time recited would depend on the desired TSAC drop after filtration. Godawat et al. teach that their method can produce an alkaline phosphatase with a TSAC of 2.1 to 4.3 mol/mol (page 41, paragraph [00143]). Therefore, if the desired TSAC drop is no more than 0.6 to a TSAC value of 1.5 mol/mol (1.5 =2.1-0.6) after filtration and the TSAC before filtration is 2.1 mol/mol (less than 2.5 mol/mol), Figure 12 of Godawat et al. indicates a filtration step having a duration of approximately 8 hours. Similarly, if the desired TSAC drop is no more than 1.5 mol/mol to a TSAC value of 2.8 mol/mol (2.8=4.3-1.5) after filtration and the TSAC before filtration is 4.3 mol/mol (more than 3 mol/mol), Figure 12 of Godawat et al. indicates a filtration step having a duration of approximately 40 hours. The recited filtration times for the recited TSAC concentrations are dependent upon the desired TSAC concentration after filtration and/or how much TSAC drop is acceptable. For example, if the desired TSAC after filtration is no less than 2, Figure 12 of Godawat et al. clearly indicates that for an aliquot TSAC of 2.7 mol/mol, the filtration time is approximately 10 hours ( 2 = 2.7 -0.7; 0.7 is the TSAC drop). If the desired TSAC after filtration is no less than 2, Figure 12 of Godawat et al. clearly indicates that for an aliquot TSAC of 3 mol/mol, the filtration time is approximately 23 hours ( 2= 3 -1; 1 is the TSAC drop). Similarly, if the desired TSAC after filtration is no less than 2, and the TSAC for the aliquot is 3.5 mol/mol, Figure 12 of Godawat et al. clearly indicates a filtration time of approximately 40 hours (2=3.5-1.5; 1.5 is the TSAC drop). One of ordinary skill in the art has a reasonable expectation of success at carrying out the method of Godawat et al. as recited because all the steps required to practice the claimed method using the filtration times and TSAC concentrations recited are described by Godawat et al. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
SEQ ID NO: 1
BGT49563
ID BGT49563 standard; protein; 726 AA.
XX
AC BGT49563;
XX
DT 31-OCT-2019 (first entry)
XX
DE Recombinant alkaline phosphatase fusion protein (Asfotase alfa), SEQ 1.
XX
KW Alkaline phosphatase; Asfotase alfa; IgG1; Immunoglobulin G1;
KW bone disease; enzyme deficiency; enzyme production; fusion protein;
KW hypophosphatasia; metabolic-gen.; osteopathic; protein therapy;
KW recombinant protein; therapeutic.
XX
OS Homo sapiens.
OS Synthetic.
OS Unidentified.
XX
FH Key Location/Qualifiers
FT Modified-site 123
FT /note= "Asn is glycosylated"
FT Modified-site 213
FT /note= "Asn is glycosylated"
FT Modified-site 254
FT /note= "Asn is glycosylated"
FT Modified-site 286
FT /note= "Asn is glycosylated"
FT Modified-site 413
FT /note= "Asn is glycosylated"
FT Region 486..487
FT /note= "Linker"
FT Modified-site 564
FT /note= "Asn is glycosylated"
FT Region 715..716
FT /note= "Linker"
XX
CC PN WO2019190752-A1.
XX
CC PD 03-OCT-2019.
XX
CC PF 13-MAR-2019; 2019WO-US022102.
XX
PR 30-MAR-2018; 2018US-0650583P.
XX
CC PA (ALXI ) ALEXION PHARM INC.
XX
CC PI Godawat R, Dewitt M, Sui S, Rajendran S;
XX
DR WPI; 2019-83283W/00.
XX
CC PT Producing recombinant alkaline phosphatase, involves inoculating or
CC PT culturing Chinese hamster ovary cells in culture medium, isolating
CC PT phosphatase, performing additional protein purification step, and
CC PT subjecting to chromatography.
XX
CC PS Claim 48; SEQ ID NO 1; 85pp; English.
XX
CC The present invention relates to a novel method for producing recombinant
CC alkaline phosphatase. The method involves: (a) inoculating Chinese
CC hamster ovary (CHO) cells expressing recombinant alkaline phosphatase in
CC culture medium; (b) culturing the CHO cells in culture medium; (c)
CC isolating the recombinant alkaline phosphatase from the cell culture of
CC (c) by at least one purification step to form harvest clarified culture
CC fluid (HCCF) with a total sialic acid content (TSAC) of 2.1-4.3 mol/mol;
CC (d) performing at least one additional protein purification step to form
CC a filtration pool (UFDF), where the UFDF is held at a temperature of 13-
CC 27 degree C for 1-60 hours, and at a protein concentration of 1.7-5.3 g/l
CC ; and (e) subjecting the UFDF to at least one chromatography step to
CC obtain partially purified recombinant alkaline phosphatase, where the
CC recombinant alkaline phosphatase has a TSAC of 0.7-3.5 mol/mol. The
CC invention also provides: a method for using recombinant alkaline
CC phosphatase to increase cleavage of inorganic pyrophosphate (PPi) in a
CC subject; a method for controlling TSAC in a TSAC-containing recombinant
CC protein; a method for controlling glycosidase activity in mammalian cell
CC culture; and a method for treating a subject suffering from a condition
CC associated with alkaline phosphatase deficiency. The method is also
CC useful for treating diseases, preferably diseases having skeletal
CC manifestations, such as hypophosphatasia. The present sequence is a
CC fusion protein construct comprising a soluble catalytic domain of human
CC tissue non specific alkaline phosphatase (TNSALP) and a human
CC immunoglobulin G1 Fc domain a deca-aspartate peptide.
XX
SQ Sequence 726 AA;
ALIGNMENT:
Query Match 100.0%; Score 3886; Length 726;
Best Local Similarity 100.0%;
Matches 726; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 LVPEKEKDPKYWRDQAQETLKYALELQKLNTNVAKNVIMFLGDGMGVSTVTAARILKGQL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 LVPEKEKDPKYWRDQAQETLKYALELQKLNTNVAKNVIMFLGDGMGVSTVTAARILKGQL 60
Qy 61 HHNPGEETRLEMDKFPFVALSKTYNTNAQVPDSAGTATAYLCGVKANEGTVGVSAATERS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 HHNPGEETRLEMDKFPFVALSKTYNTNAQVPDSAGTATAYLCGVKANEGTVGVSAATERS 120
Qy 121 RCNTTQGNEVTSILRWAKDAGKSVGIVTTTRVNHATPSAAYAHSADRDWYSDNEMPPEAL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 RCNTTQGNEVTSILRWAKDAGKSVGIVTTTRVNHATPSAAYAHSADRDWYSDNEMPPEAL 180
Qy 181 SQGCKDIAYQLMHNIRDIDVIMGGGRKYMYPKNKTDVEYESDEKARGTRLDGLDLVDTWK 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SQGCKDIAYQLMHNIRDIDVIMGGGRKYMYPKNKTDVEYESDEKARGTRLDGLDLVDTWK 240
Qy 241 SFKPRYKHSHFIWNRTELLTLDPHNVDYLLGLFEPGDMQYELNRNNVTDPSLSEMVVVAI 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 SFKPRYKHSHFIWNRTELLTLDPHNVDYLLGLFEPGDMQYELNRNNVTDPSLSEMVVVAI 300
Qy 301 QILRKNPKGFFLLVEGGRIDHGHHEGKAKQALHEAVEMDRAIGQAGSLTSSEDTLTVVTA 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 QILRKNPKGFFLLVEGGRIDHGHHEGKAKQALHEAVEMDRAIGQAGSLTSSEDTLTVVTA 360
Qy 361 DHSHVFTFGGYTPRGNSIFGLAPMLSDTDKKPFTAILYGNGPGYKVVGGERENVSMVDYA 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 DHSHVFTFGGYTPRGNSIFGLAPMLSDTDKKPFTAILYGNGPGYKVVGGERENVSMVDYA 420
Qy 421 HNNYQAQSAVPLRHETHGGEDVAVFSKGPMAHLLHGVHEQNYVPHVMAYAACIGANLGHC 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 HNNYQAQSAVPLRHETHGGEDVAVFSKGPMAHLLHGVHEQNYVPHVMAYAACIGANLGHC 480
Qy 481 APASSLKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 APASSLKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV 540
Qy 541 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE 600
Qy 601 KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT 660
Qy 661 TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKDIDDDD 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKDIDDDD 720
Qy 721 DDDDDD 726
||||||
Db 721 DDDDDD 726
Double Patenting
Claims 1-3, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36-38 were rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,352,612. In view of the amendment of claim 1, which now requires taking an aliquot at day 6 to 8 after inoculation, and subjecting the aqueous culture medium to a filtration step to obtain a bulk drug solution (BDS), wherein the filtration step has a duration of less than 9 hours if the TSAC concentration of the aliquot is less than 2.5 mol/mol, wherein the filtration step has a duration of 10-14 hours if the TSAC concentration of the aliquot is 2.5-2.7 mol/mol, wherein the filtration step has a duration of 23-27 hours if the TSAC concentration of the aliquot is 2.8-3.0 mol/mol, or wherein the filtration step has a duration of 38-42 hours if the TSAC concentration of the aliquot is greater than 3.0 mol/mol, this rejection is hereby withdrawn.
Claims 1-3, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36, 38 remain rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-17, 21-22 of U.S. Patent No. 11, 913,039.
This rejections has been discussed at length in the prior Office action. It is maintained for the reasons of record and those set forth below.
Applicant argues that the claims of U.S. Patent No. 11, 913,039 do not teach or suggest filtration step (f) of the present claims. Applicant states that filtration step (f) may be varied as a function of TSAC content that is determined from an aliquot of the aqueous culture medium obtained during the fermentation step. Applicant states that the description of U.S. Patent No. 11, 913,039 does not teach or suggest filtration step (f) of the present claims, particularly because the claims of the U.S. Patent No. 11, 913,039 do not teach or suggest any hold time parameters that occur after the harvest step as a function of the TSAC concentration measured from day 6 to day 8 of fermentation. Applicant concludes that the claims of the ‘039 patent do not teach or suggest each and every limitation of the method of the present claims.
Applicant’s arguments have been fully considered but not deemed persuasive to overcome the instant rejection. As correctly pointed out by Applicant, the specification of U.S. Patent No. 11, 913,039 corresponds to the specification of WO 2019/190752 (Godawat et al.) previously discussed.
Claims 1-3, 5-9, 14, 16, 18, 21, 24, 26, 28, 29, 31, 36, 38 of the instant application are directed in part to a method for producing a recombinant alkaline phosphatase, wherein said recombinant alkaline phosphatase has at least 90% sequence identity to the polypeptide of SEQ ID NO: 1, wherein said method comprises inoculating a bioreactor having a volume of at least 2 L to 20000 L which comprises a culture medium that is CD DG44 or SFM4CHO with a CHO cell that expresses the recombinant alkaline phosphatase, obtaining an aqueous culture medium comprising the recombinant alkaline phosphatase, obtaining an aliquot from the aqueous culture medium at day 6 to day 8 after inoculation to determine the total sialic content (TSAC) molar concentration per mole of the recombinant alkaline phosphatase in the aliquot, harvesting the aqueous culture medium, and subjecting the aqueous culture medium to a filtration step to obtain a bulk drug solution (BDS), wherein the filtration step has a duration of less than 9 hours if the TSAC concentration is less than 2.5 mol/mol, wherein the filtration step has a duration of 10-14 hours if the TSAC concentration is 2.5-2.7 mol/mol, wherein the filtration step has a duration of 23-27 hours if the TSAC concentration is 2.8-3.0 mol/mol, wherein the filtration step has a duration of 38-42 hours if the TSAC concentration is greater than 3.0 mol/mol, wherein the filtration step is performed at a temperature of 15 C to 25 C, wherein the determination of TSAC requires acid hydrolysis to release the TSAC, wherein the aliquot is centrifuged and the supernatant removed, wherein the supernatant removed is applied to a Protein A column, wherein the BDS is lyophilized. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation.
Claims 1-17, 21-22 of U.S. Patent No. 11, 913,039 are directed in part to a method of producing recombinant alkaline phosphatase comprising: (I) (a) inoculating Chinese Hamster Ovary (CHO) cells expressing recombinant alkaline phosphatase; (b) culturing the CHO cells in culture medium; (c) isolating the recombinant alkaline phosphatase from the culture medium by at least one purification step to form harvest clarified culture fluid (HCCF) with a total sialic acid content (TSAC) of about 2.1 mol/mol to about 4.3 mol/mol; (d) performing at least one additional protein purification step to form a filtration pool (UFDF), wherein the UFDF is held at a temperature of about 13° C. to about 27° C. for about 14 hours to about 42 hours, and at a protein concentration of about 2.0 g/L to about 4.3 g/L to reduce TSAC loss; and (e) subjecting the UFDF to at least one chromatography step to obtain partially purified recombinant alkaline phosphatase; and (f) recovering the recombinant alkaline phosphatase from the UFDF, wherein the recombinant alkaline phosphatase has a TSAC of about 1.2 mol/mol to about 3.0 mol/mol; or (II) (a) inoculating CHO cells expressing recombinant alkaline phosphatase; (b) culturing the CHO cells in culture medium to produce a cell culture; (c) adding a nutrient supplement to the culture medium; (d) isolating the recombinant alkaline phosphatase from the culture medium by at least one purification step to form a filtration pool (Ultrafiltration/Diafiltration UFDF), wherein the UFDF is held at a temperature of about 13° C. to about 27° C. for about 14 hours to about 42 hours, and at a protein concentration of about 2.0 g/L to about 4.3 g/L to reduce TSAC loss; and (e) recovering the recombinant alkaline phosphatase from the UFDF, wherein the recombinant alkaline phosphatase in the UFDF has a TSAC of about 1.2 mol/mol to about 3.0 mol/mol, wherein the culturing step is performed in a bioreactor having a volume of 0.25 L to 25000 L, and wherein the recombinant alkaline phosphatase comprises SEQ ID NO: 1. SEQ ID NO: 1 of U.S. Patent No. 11, 913,039 is identical to SEQ ID NO: 1 of the instant application.
The specification of U.S. Patent No. 11, 913,039 specifically discloses measuring TSAC before and after harvest (Example 4, TSAC Measurement Before and After Harvest) as a preferred embodiment of the claimed method. The specification of U.S. Patent No. 11, 913,039 discloses taking TSAC samples of the cell culture fluid (CCF) before harvest at the end of the production bioreactor run, harvesting at 200-288 hours (page 38, Harvest) and maintaining a constant temperature for 40-200 hours after inoculation, which is the culturing time. Therefore, the specification of U.S. Patent No. 11, 913,039 teach measuring TSAC in an aliquot at approximately 8 days (200 hours; end of the production bioreactor run) after inoculation and culturing times that encompass 144-192 hours (6-8 days) after inoculation. The specification of U.S. Patent No. 11, 913,039 states that the prior art suggests that delaying harvesting time was associated with lower viability and TSAC decline. The specification of U.S. Patent No. 11, 913,039 discloses purification of samples taken for TSAC determination with a protein A column and the use of acid hydrolysis for determination of TSAC as a preferred embodiment of the method by which TSAC is determined. The specification of U.S. Patent No. 11, 913,039 also discloses centrifugation as one of the preferred embodiments of the method by which the harvest clarified culture fluid is obtained. The specification of U.S. Patent No. 11, 913,039 disclose in Figure 10 that TSAC decreases significantly during ultrafiltration and provide a JMP model created using data collected of TSAC as a function of hold time (filtration time) as well as a prediction profiler shown in Figure 12. The specification of U.S. Patent No. 11, 913,039 discloses that the data collected suggests reducing the range of the hold time of the ultrafiltration step to 14-42 hours which is the filtration time recited in claim 1 of U.S. Patent No. 11, 913,039. Figure 12 of U.S. Patent No. 11, 913,039 shows that for (i) a TSAC drop of 1 mol/mol, the hold time is approximately 23 hours, (ii) a TSAC drop of 0.7 mol/mol, the hold time is approximately 10 hours, (iii) a TSAC drop of 1.5 mol/mol, the hold time is approximately 40 hours, and (iv) a TSAC drop of less than 0.6 mol/mol, the hold time is approximately 8 hours. Therefore, Figure 12 shows that the larger the hold time, the larger the TSAC drop.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to take an aliquot from the aqueous culture medium at day 6 to day 8 after inoculation to determine the total sialic content (TSAC) molar concentration per mole of the recombinant alkaline phosphatase in the aliquot, harvesting the aqueous culture medium, and subjecting the aqueous culture medium to a filtration step to obtain a bulk drug solution (BDS), wherein the filtration step has a duration of less than 9 hours if the TSAC concentration is less than 2.5 mol/mol, wherein the filtration step has a duration of 10-14 hours if the TSAC concentration is 2.5-2.7 mol/mol, wherein the filtration step has a duration of 23-27 hours if the TSAC concentration is 2.8-3.0 mol/mol, wherein the filtration step has a duration of 38-42 hours if the TSAC concentration is greater than 3.0 mol/mol, in the method of claims 1-17, 21-22 of U.S. Patent No. 11, 913,039. One of skill in the art would have been motivated to add a step of taking an aliquot from the aqueous medium 6-8 days after inoculation to determine the TSAC content of the sample for the benefit of determining based on the TSAC the duration of the filtration step since Figure 12 provides a prediction tool regarding the length of the filtration step based on TSAC drop. As indicated above, the step of measuring TSAC prior to harvest is a preferred step of the claimed method. The specification of U.S. Patent No. 11, 913,039 discloses culturing times that encompass 6-8 days. One of skill in the art would have been motivated to (a) filtrate for less than 9 hours if the TSAC of the aliquot is less than 2.5 mol/mol, (b) filtrate for 10-14 hours if the TSAC of the aliquot is 2.5 mol/mol-2.7 mol/mol, (c) filtrate for 23-27 hours if the TSAC of the aliquot is 2.8-3 mol/Mol, and (d) filtrate for 38-42 hours if the TSAC of the aliquot is more than 3 mol/mol, because the claims of U.S. Patent No. 11, 913,039 require a TSAC after filtration of 1.2-3 mol/mol. The prediction tool of Figure 12 of U.S. Patent No. 11, 913,039 indicates that if the desired TSAC after filtration is, for example, 2 mol/mol (value between 1.2-3 mol/mol), and the aliquot has a TSAC of 2.7 mol/mol (value between 2.1-4.3 mol/mol), the filtration time is approximately 10 hours ( 2 = 2.7 -0.7; 0.7 is the TSAC drop). If the desired TSAC after filtration is no less than 2, Figure 12 of .S. Patent No. 11, 913,039 indicates that for an aliquot TSAC of 3 mol/mol (value between 2.1-4.3 mol/mol), the filtration time is approximately 23 hours ( 2= 3 -1; 1 is the TSAC drop). Similarly, if the desired TSAC after filtration is no less than 2, and the TSAC for the aliquot is 3.5 mol/mol (value between 2.1-4.3 mol/mol), Figure 12 of .S. Patent No. 11, 913,039 indicates a filtration time of approximately 40 hours (2=3.5-1.5; 1.5 is the TSAC drop). While the claims of U.S. Patent No. 11, 913,039 provides ranges for the TSAC of the harvested medium and the filtration times, the predictor of Figure 12 of U.S. Patent No. 11, 913,039 provides specific filtration times for specific TSAC concentrations prior filtration and specific TSAC concentrations after filtration, thus rendering the specific filtration times for the recited TSAC concentrations obvious. Therefore, the method of claims 1-3, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36, 38 of the instant application as interpreted is deemed an obvious variation of the method of claims 1-17, 21-22 of U.S. Patent No. 11, 913,039 in view of the preferred embodiments disclosed and the filtration times predicted by Figure 12 of U.S. Patent No. 11, 913,039.
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Conclusion
No claim is in condition for allowance.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to DELIA M RAMIREZ, Ph.D., whose telephone number is (571) 272-0938. The examiner can normally be reached on Monday-Friday from 8:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert B. Mondesi, can be reached at (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/DELIA M RAMIREZ/Primary Examiner, Art Unit 1652
DR
September 3, 2026
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