DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/30/2025 has been entered.
Claims 1, 5-8, 35 and 54-59 are pending in this application.
Applicant’s amendment to the claims filed 06/30/2025 is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Applicant’s remarks filed on 06/30/2025 in response to the final rejection mailed on 01/16/2025 is acknowledged and has been fully considered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 05/05/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the examiner.
Claim Objections
The objection to claim 1 is withdrawn in view of the amendment to claim 1 to recite “two heavy chains and a light chain (HHL), two heavy chains (HH), a heavy chain and a light chain (HL), a heavy chain (H), a light chain (L)”.
Claim 1 is objected to for the phrase “w or w/o 5.0 mM cysteine” in line 7. In the interest of improving claim form, Applicant should consider an amendment to recite “with or without 5.0 mM cysteine”.
Claim 1 is objected to for the phrases “a redox pair selected from […] (3) 0.3 mM cystine and 5.0 mM glutathione; w or w/o 5.0 mM cysteine; (4) 0.3 mM cystine and 5.0 mM glutathione and 5.0 mM cysteine”. In the interest of improving claim form, Applicant should consider an amendment to delete one of the two options (3) or (4), or distinguish the two options as distinct from each other, as option (3) encompasses option (4) and renders it a duplicate.
Claim 54 is objected to for the phrase “wherein the method further purifies or isolates the full antibody molecules from the starting solution”. In the interest of improving claim form, Applicant should consider an amendment to recite “wherein the method further comprises purifying or isolating the full antibody molecules from the starting solution”.
Claim 56 is objected to for the phrase “The method of claims 1”. ”. In the interest of improving claim form, Applicant should consider an amendment to recite “The method of claim 1”.
Claim Rejections - 35 USC § 112(b)
The rejection of claim 39 under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention is withdrawn in view of the cancelation of claim 39.
Claims 5-8 and 58-59 are newly rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 5 (claims 6-8 dependent therefrom) is indefinite for the phrase “(v) any combination thereof, in the starting solution”, as it is unclear whether the limitation of “in the starting solution” is intended to apply to only option (v), or is intended to apply to all of options (i)-(v) recited in the claim.
Claims 6-8 are indefinite for the phrase “The method of claim 5, wherein the redox buffer is admixed if…” corresponding to the conditional limitations on “the free thiol concentration” in claim 6, “the concentration of the partial molecules” in claim 7, and “the purity or concentration of the full molecules” in claim 8, as the phrase in conjunction with the conditional limitations encompasses situations wherein the redox buffer is not admixed if the conditions are not met. As claims 6-8 encompass situations where the admixing of the redox buffer is not required, and claim 1 requires the active step of “admixing the starting solution comprising the partial molecules with a redox buffer”, the scopes of claims 6-8 are rendered indefinite.
Claims 58-59 recite the term “about”, which is a relative term which renders the claims indefinite. The term "about" is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Therefore the limitations on the pH of the redox buffer are rendered indefinite by the use of the term.
Response to Remarks: beginning on p 5 of Applicant’s response to rejections under 35 USC 112(b); Applicant in summary contends the cancelation of claim 39 obviates the rejection.
Applicant’s response is acknowledged and the rejection has been withdrawn. Applicant’s amendments to include new claims have resulted in new grounds of rejection set forth above.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 11, 23, 26, 37, 39, 41 and 54-55 under 35 U.S.C. 102(a)(1) as being anticipated by Dillon et al. (WO 2006/047430 A2; cited on the IDS submitted 10/13/2022; herein referred to as Dillon) is withdrawn because Dillon does not teach the newly added amendment to claim 1 to recite “a redox buffer having a pH from 8 to 10 and comprising a redox pair selected from (1) 0.3 mM cystine alone; (2) 0.3 mM cystine and 5.0 mM cysteine; (3) 0.3 mM cystine and 5.0 mM glutathione; w or w/o 5.0 mM cysteine; (4) 0.3 mM cystine, 5.0 mM glutathione and 5.0 mM cysteine; or (5) 0.15 mM cystine, 2.5 mM cysteine and 2.5 mM glutathione”.
Claim Rejections - 35 USC § 103
Claims 1, 5-8, 35 and 54-59 are rejected under 35 U.S.C. 103 as being unpatentable over Dillon.
The instant rejection is maintained from the previous Office Action and any newly recited portions are necessitated by claim amendment.
Claim 1 is drawn to a method for converting partial antibody molecules comprising HHL, HH, HL, H, L, or any combination thereof, to full antibody molecules in a starting solution, a method for purifying or isolating full molecules from a starting solution comprising partial molecules, the method comprising admixing the starting solution comprising partial molecules with a redox buff having a pH from 8 to 10 and comprising a redox pair selected from
0.3 mM cystine alone;
0.3 mM cystine and 5.0 mM cysteine;
0.3 mM cystine and 5.0 mM glutathione, with or without 5.0 mM cysteine;
0.3 mM cystine, 5.0 mM glutathione and 5.0 mM cysteine; or
0.15 mM cystine, 2.5 mM cysteine and 2.5 mM glutathione,
wherein the redox buffer re-oxidizes the partial molecules to full molecules on a substrate,
wherein the substrate is a Protein A affinity chromatography resin,
wherein the starting solution is selected from a harvested cell culture fluid supernatant, a lysate, a filtrate, an eluate, or a purified material.
The claims are being interpreted based on the definitions of “partial” and “full” molecules set forth in the instant specification, wherein “partial molecule” is defined as a polypeptide component of a larger preferred molecule [para 0115], and “full molecule” is defined as a complete protein of interest [para 0116].
Dillon discusses methods for refolding recombinant antibodies [title], wherein Dillon discloses that antibodies are comprised of heavy chains and light chains connected by disulfide bonds between the chains that form the full antibody molecule from partial antibody molecules [Fig. 43].
Regarding claim 1, Dillon discloses a method of refolding proteins to produce improved pharmaceutical and crystallization properties using the addition of reduction/oxidation (redox) coupling reagents to facilitate the formation of native-like disulfide bonds in the recombinant proteins [p 5, lines 5-10], wherein the formation of native-like disulfide bonds is the oxidation of partial molecules to full molecules. Dillon discloses this activity to be carried out in solution that is preferably buffered [p 37, lines 12-15], and that the redox coupling reagents include reducing agents are free thiols [p 37, line 24] paired with oxidized thiols such as glutathione and oxidized glutathione [p 38, lines 20-24]. As Dillon discloses a method of refolding antibodies, wherein full antibodies are comprised of 2 heavy chains and 2 light chains [Fig. 43], the method of Dillon is considered to encompass the conversion of partial antibody molecules comprising HHL, HH, HL, H, L, or any combination thereof as recited in the claim. Dillon further discloses the method of refolding recombinant antibodies comprises contacting a purified preparation of an IgG antibody with a redox coupling reagent [claim 1], which is considered to encompass a starting solution of purified material as recited in the claim.
Regarding claim 1 and the limitation of redox pairs, Dillon teaches a method of refolding using redox reagents using cysteine and cystine [p 37, lines 23-34] at concentration ranges of about 0.05 mM to about 50 mM free thiol [p 39, lines 17-19] and ratios of about 1:1 to about 100:1 reduced:oxidized thiol [p 39, lines 23-25] that encompass the 5 mM cysteine (reduced thiol) and 0.3 mM cystine (oxidized thiol) recited in option 2. MPEP 2144.05(I) states in the case where the claimed ranges or amounts “overlap or lie inside ranges disclosed by the prior art”, a prima facie case of obviousness exists. As the ranges taught by Dillon encompass the concentrations of 5 mM cysteine and 0.3 mM cystine recited in the claim, the teachings of Dillon correspond to the limitations of redox pair concentrations in the claim.
Regarding claim 1 and the limitation of redox buffer pH, Dillon teaches the use of 200 mM Tris at pH 8 [p 54, lines 6-8].
Regarding claim 1 and the limitation of the substrate Protein A affinity chromatography resin, Dillon teaches that contacting the recombinant protein with redox coupling reagents occurs in preferably a buffered solution and can also occur on a solid support, e.g., on an affinity column or a chromatography matrix [p 37, lines 12-15], and teaches the use of Protein A as an affinity column [p 78, ln 23], which corresponds to a Protein A affinity chromatography resin.
In view of Dillon, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to refold recombinant antibodies by contacting a purified preparation of an antibody with a redox coupling reagent comprising different ratios of redox pair at pH 8 on a Protein A affinity chromatography resin substrate. One of ordinary skill in the art would have been motivated to produce full antibody molecules from partial antibody molecules because Dillon teaches methods for refolding recombinant antibodies comprised of heavy and light chains comprising refolding proteins via contact with redox coupling reagents to facilitate the formation of native-like disulfide bonds in the recombinant proteins, as well as the concentrations of redox pairs to use, the pH of the buffer to use, that the refolding can occur on a solid support such as an affinity column, and that an example of an affinity column is a Protein A affinity column. One of ordinary skill in the art would have had a reasonable expectation of success because of the express teachings of Dillon.
Regarding claim 5, the claim is being interpreted such that the limitation of “in the starting solution” is only required for “any combination thereof” in option (v) of claim 5. As such, Dillon teaches their method includes the contacting of a preparation of recombinant protein that is made up of a heterogeneous mixture of at least two configurational isomers to a redox coupling reagent followed by determining the relative proportion of the desired configurational isomer in the mixture [p 31, lines 20-24].
In the interest of compact prosecution, and based on the alternative interpretation that the recitation of “in the starting solution” applies to all of options (i) to (v) of claim 5, Dillon teaches related to the material to be reformed that “the desired degree of final purity depends on the intended use of the polypeptide, and that a relatively high degree of purity is desired when the polypeptide is to be administered in vivo, for example. In such case, the polypeptides are purified such that no polypeptide bands corresponding to other polypeptides are detectable upon analysis by SDS-polyacrylamide gel electrophoresis (SDS-PAGE)… the polypeptide of the invention is purified to substantial homogeneity” [p 37, lines 1-9].
Regarding claim 6, the claim is being interpreted as meaning the limitation “the free thiol concentration is higher than 100 µM” is directed to the redox buffer. Dillon teaches a method of refolding using redox reagents using cysteine and cystine [p 37, lines 23-34] at concentration ranges of about 0.05 mM to about 50 mM free thiol [p 39, lines 17-19], which encompasses a free thiol concentration higher than 100 µM.
Regarding claims 7-8, Dillon teaches the method of reforming antibodies discussed in the rejection of claim 1, and related to the material to be reformed Dillon teaches that “the desired degree of final purity depends on the intended use of the polypeptide, and that a relatively high degree of purity is desired when the polypeptide is to be administered in vivo, for example. In such case, the polypeptides are purified such that no polypeptide bands corresponding to other polypeptides are detectable upon analysis by SDS-polyacrylamide gel electrophoresis (SDS-PAGE)… the polypeptide of the invention is purified to substantial homogeneity” [p 37, lines 1-9]. The SDS-PAGE recited in the reference is interpreted to encompass the capillary gel electrophoresis recited in the claims, and in light of evidence to suggest otherwise, SDS-PAGE is run in non-denaturing conditions (such as without reductants common in the field such as beta-mercaptoethanol or chaotropic salts such as Urea or Guanidinium HCl). Dillon further teaches that the contact between the redox coupling agent and the polypeptide are sufficient to increase the relative proportion of the desired conformation, including an increase of the desired proportion that includes from a 10% increase to an 80% increase. As such, Dillon teaches that the antibody reforming method is carried out on polypeptides with certain degree of purity suitable to the intended use, in which an example is given for determining the suitability of the purity corresponding to the relative abundance a desired relative amount, wherein an 80% increase in full molecule formation corresponds to a starting concentration of partial molecules above 10% as recited in claim 7, and an 20% increase in full molecule formation corresponds to a starting concentration of full molecules that is less than 90% as recited in claim 8.
Regarding claims 35, Dillon teaches that contacting the recombinant protein with redox coupling reagents occurs in preferably a buffered solution and can also occur on a solid support, e.g., on an affinity column or a chromatography matrix [p 37, lines 12-15]. One of skill in the art would reasonably expect that while the contacting of a protein with redox reagents might occur while the protein is on an affinity column, the buffered redox solution of Dillon as described above can be used to contact the protein affixed to the affinity column. Additionally, it is noted that the teaching of Dillon for the redox coupling to occur in a buffered solution and also on a solid support does not establish the buffered solution and solid support to be mutually exclusive. Put another way, the teaching of Dillon encompasses a solid support that is in contact with a buffer.
Regarding claims 54 and 56-57, Dillon discloses the method described in the rejection of claim 1 above [p 5, lines 5-10 of the reference] and further recites the method results in a refolded IgG2 antibody with structural homogeneity [p 52, lns 4-8] and with higher activity than IgG2 bulk antibody prepared without redox reagents to promote refolding [p 52, lns 16-20], wherein the structural homogeneity is considered to correspond to a single structure of a full antibody molecule rather than heterogeneous structures comprised of partial antibodies of varying sizes, and wherein the purification of a full antibody molecule is further indicated by the increased activity relative to non-refolded bulk material.
Regarding claim 55, Dillon discloses the method described in the rejection of claim 1 above [p 5, lines 5-10 of the reference] and further recites the method comprises contacting a purified preparation of IgG antibody with a reduction/oxidation coupling reagent [claim 1], wherein the reduction/oxidation coupling agent comprises reduced and oxidized glutathione [claim 12] or cysteine and cystine [claim 14]. The introduction of the reduced glutathione or cysteine in the starting solution of a purified preparation of IgG antibody is understood in the art to reduce the disulfide bonds between cysteine residues of the peptides, which also serves to prevent the formation disulfide bonds between light and heavy chains that form partial antibody fragments.
Regarding claims 58-59, Dillon teaches the use of 200 mM Tris at pH 8 [p 54, lines 6-8].
Therefore, the method of claims 1, 5-8, 35 and 54-59 would have been obvious to one of ordinary skill in the art before the effective filing date.
Response to remarks: beginning p 5 of Applicant’s response to rejections under 35 USC 102 and p 5 of Applicant’s response to rejections under 35 USC 103; Regarding 102 rejections, Applicant in summary contends that Dillon fails to disclose all of the features the amended claim 1 in a single embodiment; Regarding 103 rejections, Applicant in summary contends Dillon does not teach the use of Protein A resin to carry out the method of the amended claims in combination with a redox buffer at the recited pH range and with the recited redox pairs.
Applicant’s remarks regarding the disclosure of Dillon in a single embodiment is acknowledged, and the 102 rejection is withdrawn above.
Applicant’s remarks regarding rejections under 103 are considered and found not convincing. As described in more detail in the rejection above, Dillon teaches a method of refolding recombinant antibodies from a purified preparation as a starting material, along with the suggested redox pairs and concentrations that are considered obvious as encompassing the claimed concentrations according to MPEP 2144.05(I). Dillon additionally teaches the use of a redox buffer at the claimed pH range, as well as the use of an affinity column in the method, wherein a Protein A affinity column is given as an example of an affinity column.
Applicant’s assertion that “the present invention is based on the unexpected technical effect” citing the example in the instant specification [para 0195] is interpreted an allegation of unexpected results. The example cited by Applicant in [para 0195] of the specification corresponds to Table 2 summarizing the purify of re-oxidation experiments carried out at different concentrations of redox reagents cysteine, cystine and glutathione (GSH) at pH 7, 8 and 10, which are results from the reoxidation of mAB-T as disclosed in [para 0191].
According to MPEP 716.02(e), unexpected results must be compared with the closest prior art. As the example given in the specification is not compared to any prior art, the allegations of unexpected results do not satisfy MPEP 716.02(e). According to MPEP 716.02(d), unexpected results must be commensurate in scope with the claimed invention. As the example given by Applicant involves the refolding of mAB-T at pH 7, 8 and 10, and the claims are drawn to converting partial antibody molecules comprising HHL, HH, HL, H, L or any combination thereof to full antibody molecules, comprising a redox buffer with a pH from 8 to 10, the results cited by Applicant are considered not commensurate in scope with the claimed invention, and do not satisfy the requirements of MPEP 716.02(d). Therefore, the allegation of unexpected results is considered insufficient to rebut a prima facie case of obviousness.
Conclusion
Status of the Claims:
Claims 1, 5-8, 35 and 54-59 are pending.
Claims 1, 5-8, 35 and 54-59 are rejected.
No claim is in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH SPANGLER whose telephone number is (571)270-0314. The examiner can normally be reached M-F 7:30 am - 4:30 pm.
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/JOSEPH R SPANGLER/
Examiner
Art Unit 1656
/David Steadman/Primary Examiner, Art Unit 1656