Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/18/2025 has been entered.
DETAILED ACTION
Claim 8 is canceled. Claims 1-7 and 9-26 are pending and are entitled to an effective filing date of 30 April 2014.
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 2, 9 and 15 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.
Claim 2 recites wherein the purification of the target protein comprises inactivation of virus in said sample, which renders the claim indefinite because in one interpretation the claim requires any of step (i), (ii) or (iii) in claim 1 to comprise an inactivation of virus in said sample, and under an alternative interpretation, the claim requires the purification method of claim 1 to further comprise an additional step of inactivation of virus in said sample. To obviate this rejection, claim 2 can be amended to replace “comprises” with “further comprises”.
Claim 9 recites the limitation “the virus” in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 9 depends from claim 1, which does not require a virus. Therefore, it is unclear whether claim 9 intends to reference a specific virus or any virus.
Claim 15 recites “the target protein” in the last line. There is insufficient antecedent basis for this limitation in the claim. It is unclear whether the target protein is required to be the coagulation factor, antibody or Fab thereof as recited in line 2, because the claim does not recite the coagulation factor, antibody or Fab thereof as alternatives of target proteins. Therefore, in one interpretation step (iii) encompasses eluting any target protein, and under an alternative interpretation step (iii) requires eluting the coagulation factor, antibody or Fab thereof. To obviate this rejection, claim 15 can be amended to replace “the purification of a protein” in line 1 with “the purification of a target protein”, and to further replace “one or more of said proteins” in line 3 with “one or more of said target proteins”; alternatively, the term “target” can be deleted from the last line.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 4 and 16 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 4 and 16 do not further limit the concentration of caprylic acid solution of claim 1 from which they depend. Claim 1 requires a caprylic acid buffer at a concentration of 1 to 50 mM in line 7. However, claim 4 recites a broader range of caprylic acid concentrations that are least 1 mM, and claim 16 recites a broader range of concentrations that are at least 2 mM. As such, claims 4 and 16 broaden the scope of the caprylic acid concentration, because claims 4 and 16 do not require the 50 mM upper limit. Furthermore it is unclear whether claim 4 intends to broaden the scope of the caprylic acid (i.e. an organic acid) component to any inorganic or organic acid.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Interpretation
Claim 1 requires three steps. In the first step, a target protein-containing sample is loaded onto a stationary phase, so as to bind the target protein to said stationary phase. The stationary phase is selected from the following chromatography columns: ion exchange, affinity, fast protein liquid and expanded bed adsorption. In the second step, the stationary phase with the bound target protein is subjected to a caprylic acid buffer solution that is at a pH so as to form free caprylic acid, and at a concentration of 1-50 mM caprylic acid, as measured in terms of free caprylic acid. According to the instant specification, caprylic acid in its free form is non-ionized and un-dissociated. See page 5 lines 18-20. The specification discloses that the concentration of non-ionized caprylic acid can be determined by the equation pH= pKa + log([caprylate]/[caprylic acid]), and the pKa of caprylic acid is 4.9. See page 16 line 11 and lines 17-18. As such, caprylate solutions at a pH of 7 or below includes the caprylic acid in its free form. In the third step, the target protein is eluted.
Claim 3 requires the same active method steps as claim 1, but the result or intended purpose of the method is to prepare a virus-free protein solution.
Claim 9 requires the caprylic acid solution to have a pH so as to inactivate any virus and not denature the target protein. The instant specification discloses that the murine leukemia virus (MuLV) can be inactivated at a pH range of 5.9 to 6.3. See page 26 lines 5-6.
Claim 15 requires three steps. In the first step, a sample comprising one or more of a coagulation factor, an antibody or a Fab thereof is loaded onto a stationary phase for affinity chromatography. In the second step, the stationary phase is subjected to 2-10 mM of caprylic acid, measured in terms of free caprylic acid, at a pH that is greater than 4.9 and less than 6.2. The claim recites “so as to inactivate and wash away viruses”, however the claim does not require the sample to include viruses; so the recitation is the result or intended purpose of the second step. In the third step, the protein is eluted.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-7, 9, 11, 13, 18 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Burton (US 8,198,407) with evidence from GE Healthcare (ÄKTAexplorer System Manual ÄKTA, 2008).
Regarding claim 1, Burton teaches a method of sequential protein isolation and purification comprising: (i) providing a plasma sample, (ii) providing a plurality of ligands each of which binds specifically to a target protein in the plasma sample, wherein each of the plurality of ligands is optionally attached to a support, (iii) contacting the plurality of ligands or ligand-support complexes with the plasma sample to allow binding of target protein, (iv) eluting the respective target proteins, and (v) isolating the target proteins. See claim 1 of Burton. Burton teaches affinity chromatography (i.e. stationary phase) conducted using ligands or ligand support complexes. See the abstract. In example 2, Burton teaches an affinity capture of plasma proteins. See column 15 line 30-31. Burton teaches preparing a column with an affinity adsorbent developed for the capture of albumin. See column 18 lines 1-4. The albumin is eluted with an elution buffer comprising 50 mM Na caprylate, pH 6.2. See column 18 lines 21-22.
Although Burton does not explicitly teach a caprylic acid buffer at a concentration of 1 to 50 mM as measured in terms of free caprylic acid, Burton teaches an elution buffer comprising 50 mM Na caprylate at a pH of 6.2. Based on the pH 6.2 = 4.9 pKa of caprylic acid + log([50 mM Na caprylate]/[caprylic acid]) equation, the caprylic acid concentration of the elution buffer taught by Burton is 2.5 mM, which meets the instantly required caprylic acid buffer concentration of 1 to 50 mM, as measured in terms of free caprylic acid.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to elute the albumin protein with the elution buffer comprising 50 mM Na caprylate at a pH of 6.2, as taught by Burton, and the process the affinity adsorbent (stationary phase) with the bound albumin (target protein) of Burton would necessarily be to subjected to 2.5 mM caprylic acid buffer.
Regarding claim 2, Burton teaches preparations subjected to at least one pathogen inactivation step. See column 4, lines 31 and 33-34. The term “pathogen” includes viruses. See column 6, lines 18 and 20-21.
Regarding claim 3, Burton teaches a method comprising: (i) providing a plasma sample, (ii) providing a plurality of ligands each of which binds specifically to a target protein in the plasma sample, (iii) contacting the plurality of ligands with the plasma sample to allow binding of target protein, and (iv) eluting the respective target proteins. See claim 1 of Burton. Burton further teaches a preparation that is substantially purified and has been subjected to at least one pathogen inactivation step. See column 4 lines 31-34. In example 2, Burton teaches preparing a column for albumin affinity capture. See column 18 lines 1-4. Burton teaches eluting albumin with an elution buffer comprising 50 mM Na caprylate, pH 6.2 (i.e. caprylic acid concentration of 2.5 mM). See column 18 lines 21-22. Burton does not teach or suggest that the plasma or albumin includes a virus. Therefore, Burton meets the instantly recited virus-free protein solution of claim 3.
Regarding claims 4, 16-17 and 21, Burton teaches an elution buffer composed of 50 mM Na caprylate (i.e. a caprylate salt) and at a pH of 6.2. See column 18 lines 22-23. As such, Burton indicates that the caprylic acid concentration in the elution buffer is 2.5 mM.
Regarding claim 5, Burton teaches a biological sample that is plasma and target proteins that include coagulation factors. See column 3 lines 34-35 and 37.
Regarding claim 6, Burton teaches animal plasma samples. See column 5 lines 18 and 20.
Regarding claim 7, Burton teaches methods for sequential protein isolation and purification from a biological sample by affinity chromatography. See the abstract. In example 2, Burton teaches an affinity capture of plasma proteins. See column 15 line 30.
Regarding claim 9, Burton teaches preparing an affinity column for the capture of albumin. See column 18 lines 1-4. Albumin is eluted with an elution buffer comprising Na caprylate at a pH of 6.2. See column 18 lines 21-22. Burton suggests that the elution conditions should not denature the target protein, unless desired. See column 10 lines 21-23. Burton teaches yielding albumin (HSA). See table 15 in column 20. Burton does not each or suggest that the HSA is denatured.
Although Burton does not explicitly teach a pH that inactivates a virus, based on the interpretation of instant claim 9 as discussed above, the pH 6.2 of Burton meets the instantly recited limitation of “a pH so as to inactivate the virus”.
Regarding claim 11, Burton suggests that the elution buffer in example 2 has a caprylic acid concentration of 2.5 mM, because Burton teaches an elution buffer that comprises 50 mM Na caprylate and is at a pH of 6.2. See column 18 lines 21-22 and the equation discussed above. Therefore, Burton meets the instantly recited limitation that requires a caprylic acid buffer concentration of 1 to 20 mM.
Regarding claim 13, Burton teaches performing all chromatography using the AKTA Explorer 100 chromatography system with fraction collectors. See column 12 lines 54-55. ÄKTA explorer 100, is a fully automated liquid chromatography system, as evidenced by GE Healthcare. See section 1.2 on page 10.
Regarding claim 18, Burton teaches target protein comprising coagulation factors, Factor VIII. See column 3 lines 34-35 and 37-38. In example 2, Burton teaches a plasma protein purification scheme that includes the affinity capture of FVIII. See column 15 lines 30-34 and 44.
Claims 10, 15, 19 and 20, and 22-26 are rejected under 35 U.S.C. 103 as being unpatentable over Burton (US 8,198,407), as applied to claims 1-7, 9,11, 13, 18 and 21 above, and further in view of Tenold (US 5,561,115).
Regarding claim 10, Burton teaches eluting albumin with an elution buffer comprising Na caprylate at a pH of 6.2. See column 18 lines 21-22. Burton suggests that elution buffers can have various pHs. See column 10 lines 5-9.
Burton does not specifically teach a pH of 6.1 or less for a caprylic acid solution.
Tenold teaches preparing albumin from a solution of plasma proteins comprising (a) employing sodium caprylate in the solution of plasma proteins at a pH of about 5.25 to 5.6 as a partitioning agent to separate albumin from the non-albumin proteins. See claim 1 of Tenold. In example 1, Tenold teaches adding sodium caprylate to an effluent to partition albumin from unwanted proteins. Tenold discloses that sodium caprylate also functions as an antiviral agent. See column 5 lines 49-54. Tenold teaches maintaining the pH about 5.3 to 5.6 in example 1. See column 5 line 60. Tenold suggests that the pH affects albumin recovery since pH levels lower than about 5.4 approach albumin’s isoelectric range. See column 5 lines 63-65.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to adjust the pH 6.2 of the elution buffer taught by Burton to a pH of about 5.25 to 5.6 as suggested by Tenold. One would be motivated to do so because Tenold suggests that such pH can improve albumin recovery. There would have been a reasonable expectation of success because Burton suggests that the pH of the elution buffer can be varied, and Tenold demonstrates separating (partitioning) albumin from unwanted proteins with sodium caprylate at pHs between 5.3 to 5.6. MPEP 2144.05(II)(A) states that “[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 15, Burton teaches affinity chromatography. See the abstract. In example 2, Burton teaches preparing a column with an affinity adsorbent developed for the capture of albumin. See column 18 lines 1-4. Burton teaches eluting albumin with an elution buffer comprising 50 mM Na caprylate at a pH of 6.2. See column 18 lines 21-22.
Burton does not teach subjecting the stationary phase to a caprylic acid solution at a pH of 4.9<pH<6.2, so as to inactivate and wash away viruses.
Tenold teaches sodium caprylate in the solution of plasma proteins at a pH of about 5.25 to 5.6 to separate albumin from the non-albumin proteins. See claim 1 of Tenold. Tenold discloses that sodium caprylate functions as an antiviral agent. See column 5 lines 52-54.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to adjust the pH 6.2 of the elution buffer taught by Burton to a pH of about 5.25 to 5.6 as suggested by Tenold, and arrive at a caprylic acid solution at a pH that meets the instantly recited 4.9<pH<6.2 limitation.
Regarding claims 19-20, and 22-26, Tenold sodium caprylate at a pH of about 5.25 to 5.6 to separate albumin from the non-albumin proteins. See claim 1 of Tenold.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to adjust the pH 6.2 of the elution buffer taught by Burton to a pH of about 5.25 to 5.6 as suggested by Tenold and arrive at a caprylic acid solution with a pH between 2-6 (relevant to instant claim 19), 3<pH≤6 (relevant to instant claim 22), 4<pH≤6 (relevant to instant claim 23), 4.5<pH≤6 (relevant to instant claim 24) 4.6≤pH<6 (relevant to instant claim 25), and 4.9<pH<6.
Claims 12 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Burton (US 8,198407), as applied to claims 1-7, 9,11, 13, 18 and 21 above, and further in view of Miekka (US 2003/0213920).
Regarding claim 12, Burton teaches samples that may be obtained from any source that potentially contains a target protein. Such sources include animals and viruses. See column 5 lines 13, 15-18. Burton teaches a plasma sample. See claim 1 of Burton. Burton teaches preparations subjected to at least one pathogen inactivation step. See column 4 lines 31 and 33-34.
Burton does not teach a sample that comprises enveloped viruses, non-enveloped virus, or both non-enveloped and enveloped viruses.
Miekka teaches plasma protein fractions containing porcine parvovirus (i.e. non-enveloped virus). See [0138]. Miekka suggests that many preparations containing albumin may contain unwanted and potentially dangerous biological contaminants or pathogens including viruses. See [0011]. Miekka suggests that most procedures for producing biological materials involve screening pathogens rather than removing or inactivating the pathogen. Materials that test positive for a biological contaminant or pathogen are merely not used. See [0012].
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to replace the plasma sample of Burton with the plasma protein fractions containing porcine parvovirus of Miekka. One would be motivated to do so because Miekka suggests that such pathogen containing sample would merely go unused in most biological production procedures; and Burton suggests using any sample source that potentially contains a target protein. There would be a reasonable expectation of success because the plasma protein fractions containing porcine parvovirus of Miekka could reasonably serve the same function as the plasma of Burton.
Regarding claim 14, Miekka teaches sterilizing preparations containing albumin to reduce the level of biological contaminants or pathogens including mycoplasmas. See the abstract, paragraph [0001]. Miekka suggests that many preparations containing albumin may contain unwanted and potentially dangerous biological contaminants or pathogens including mycoplasmas. See [0011].
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to apply the sterilization technique of Miekka to the albumin containing plasma sample of Burton. One would be motivated to do so because Miekka suggests that albumin containing preparation may contain mycoplasma pathogen. There would be a reasonable expectation of success because Burton teaches subjecting preparations to at least one pathogen inactivation step, and Miekka teaches inactivating pathogenic mycoplasma.
Response to Arguments
Applicant's arguments filed 12/18/2025 have been fully considered but they do not apply to the new grounds of rejection set forth above.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KIMBERLY C BREEN whose telephone number is (571)272-0980. The examiner can normally be reached M-Th 7:30-4:30, F 8:30-1:30 (EDT/EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, LOUISE HUMPHREY can be reached at (571)272-5543. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/K.C.B./ Examiner, Art Unit 1657