DETAILED ACTION
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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/14/2026 has been entered.
Withdrawn Rejections
The rejection of claims 4 and 25 under 112b is withdrawn in response to the amendments.
The rejection of claim 4 under 102 is withdrawn in response to the amendments. However, new grounds of rejection are set forth below.
Priority
Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT Application No. PCT/IL2020/050452, filed 04/16/2020, which claims benefit under 35 U.S.C. 119(e) to provisional application No. 62/924,204, filed 10/22/2019. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. IL268878, filed on 08/22/2019 in Israel.
Status of the Claims
Claims 1-8, 11, 14, 16-20, 25-27 and 29 are pending; claims 4, 25 and 29 are amended; claims 9-10, 12-13, 15, 21-24, 28 and 30-54 are cancelled; no claims are withdrawn; claims 1-8, 11, 14, 16-20, 25-27 and 29 are examined below.
New Claim Interpretation
Claim Interpretation
In claim 25 lines 12-16, the limitation “wherein said contacting is effected under conditions such that the antibody fragment which comprises an Fc region partitions preferentially into said aggregate relative to the antibody fragment which comprises an antigen binding region, so as to generate an antibody fragment-enriched aggregate and an antibody fragment-enriched medium” is interpreted as “having a level of salt below 100 mM” as per page 3 lines 28-29 of the specification and page 32 lines 20-25 (“At higher pH (pH 8) no Fc was observed in the supernatant but process efficiency decreased dramatically (Figure 10B, lane 7). In addition to the pH, ionic strength was found to represent an additional important parameter for regulation of the Fc domain in the supernatant (Figure 10C). At low ionic strength (e.g. 13 mM NaCl) and pH 7.4 the amount of Fc was minimal. The increase in the presence of Fc was found to be correlated with the increase in salt (Figure 10C, lanes 8-9)”).
New Rejection
Claim Rejections - 35 USC § 112
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 25-27 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 25 recites “partitions preferentially” in line 14. However, it is not clear what is meant by “partitions preferentially” because the term “preferentially” is indefinite. The term “preferentially” is indefinite because it is not clear whether the partitioning is required in the claim or not. A person having ordinary skill in the art would not be capable of recognizing the metes and bounds of the claim.
Claims 26-27 are included in this rejection because they depend from rejected claim 25 but fail to clarify the scope of patent protection sought.
Maintained Rejection
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 25 is rejected under 35 U.S.C. 102(a)(2) as being anticipated by Patchornik et al. (WO 2018/207184 A2) (Cite No. 5 of IDS filed 4/6/2022) (“Patchornik”).
The rejection of claim 25 is maintained and has been modified to address Applicant’s amendments.
Regarding claim 25, Patchornik teaches a method of isolating an antibody fragment of interest (“Methods of purifying antibodies” Title, Fig. 1, Abstract, “[t]he term "antibody" as used in this invention includes intact molecules as well as functional fragments thereof” page 9 lines 9-10) comprising: (a) contacting bathophenanthroline, a non-ionic detergent and iron ions so as to generate an aggregate comprising said bathophenanthroline, said detergent and said iron ions, wherein said non-ionic detergent is a polysorbate, a polyoxyethylene oleyl ether or octylphenol ethoxylate (“The method comprises contacting a hydrophobic chelator, a non-ionic detergent and metal ions so as to generate an aggregate comprising the hydrophobic chelator, the detergent and the metal ions” Abstract, “EXAMPLE 1… Tween-20 aggregates were obtained by mixing equal volumes of medium A and B: Medium A was prepared by the addition of 10 μL of the hydrophobic chelator bathophenanthroline (20 mM in methanol) to 90 μL of 0.25 mM Tween-20 with vigorous vortexing to a final volume of 100 μL. An equal volume of medium B, comprised of l mM FeSO4 in 20mM NaCl was then added to Medium A with vigorous vortexing” page 24 lines 15-19); (b) contacting said aggregate with a medium comprising: (i) an antibody fragment which comprises an Fc region and is devoid of an antigen binding region; and (ii) an antibody fragment which is devoid of an Fc region (“Antibody fragments can be obtained by pepsin or papain digestion of whole antibodies… an enzymatic cleavage using pepsin produces two monovalent Fab' fragments and an Fc fragment directly” page 11 lines 4 and 9-10) wherein said contacting is effected under conditions such that the antibody fragment which comprises an Fc region partitions preferentially into said aggregate relative to the antibody fragment which comprises an antigen binding region, so as to generate an antibody fragment-enriched aggregate and an antibody fragment-enriched medium; and (c) isolating said antibody fragment of interest from said fragment-enriched aggregate or from said fragment-enriched medium, thereby isolating the antibody fragment of interest (“A method of isolating an antibody is disclosed” Abstract, “20mM NaCl” page 24 lines 15-19). Note that although Patchornik fails to use the language “the antibody fragment which comprises an Fc region partitions preferentially into said aggregate relative to the antibody fragment which comprises an antigen binding region, so as to generate an antibody fragment-enriched aggregate and an antibody fragment-enriched medium”, the teaching that the antibody is a fragment that is obtained through pepsin digestion that produces an Fc fragment and two monovalent Fab' fragments, would inherently provide the partitioning of the antibody fragment which comprises an Fc region into the aggregate relative to the antibody fragment which comprises an antigen binding region producing an antibody fragment-enriched aggregate and an antibody fragment-enriched medium. Note also that although Patchornik fails to use the language “partitions preferentially”, Patchornik inherently provides preferential partitioning when teaching that “[h]uman immunoglobulin G (higG) and mouse IgG partition almost quantitatively ( ~95% by densitometry) into aggregates of non-ionic detergents, metal ions and hydrophobic chelators, whereas the majority (>85%, by densitometry) of non-IgG proteins (i.e. impurities), are rejected. The process was highly specific as it relies on the presence of the chelator and the metal” (page 1 lines 31-33 and page 2 lines 1-2). Patchornik teaches that the partitioning was “highly specific”, thereby providing the limitation “preferential partitioning”. Furthermore, note that the claim recites broadly “isolating an antibody fragment of interest…wherein said contacting is effected under conditions such that the antibody fragment which comprises an Fc region partitions preferentially into said aggregate relative to the antibody fragment which comprises an antibody binding region so as to generate an antibody fragment -enriched aggregate and an antibody fragment-enriched medium; and (c) isolating said antibody fragment of interest from said fragment enriched-aggregate or from said fragment-enriched medium” (emphasis added); therefore, the claim is not limited to an active step of the antibody fragment which comprises an Fc region partitioning into the aggregate. The claim merely limits the contacting step which is interpreted as “having a level of salt below 100 mM” as per page 3 lines 28-29 of the specification (see claim interpretation section above). In this case, given that Patchornik teaches the aggregate components (bathophenanthroline, FeSO4 and Tween-20), the medium components (Fab' fragments and an Fc fragment), and the contacting conditions below 100 mM salt (“20mM NaCl” page 24 lines 15-19), wherein antibody includes “fragments thereof” (page 9 lines 9-10), the aggregate and contacting conditions would inherently provide the partitioning of the antibody fragment which comprises an Fc region into the aggregate . The teachings of Patchornik read on the claim, i.e. Patchornik also contemplates the contacting being effected under conditions such that preferential partitioning of the antibody fragment which comprises an Fc region take place, thus anticipating the instant claim.
Maintained Rejections
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 1-3, 11, 14, 16-17, 19-20 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Patchornik et al. (WO 2018/207184 A2) (Cite No. 5 of IDS filed 4/6/2022) (“Patchornik”) in view of Brown et al. Current Opinion in Colloid & Interface Science 20 (2015) 140–150 http://dx.doi.org/10.1016/j.cocis.2015.08.002 (“Brown”)-Cite U of PTO-892 8/11/2025.
Regarding claims 1 and 3, Patchornik teaches a method of isolating an antibody (Title, Fig. 1), the method comprising: (a) contacting bathophenanthroline, a non-ionic detergent and an iron salt, so as to generate an aggregate comprising said bathophenanthroline, said detergent and iron ions of said iron salt, said non-ionic detergent being a polysorbate, a polyoxyethylene oleyl ether or octylphenol ethoxylate (page 24 lines 15-19); and (b) contacting said aggregate with a medium comprising the antibody under conditions that allow partitioning of the antibody into said aggregate, thereby isolating the antibody (Abstract and page 24 lines 15-19).
Patchornik fails to teach said iron salt being iron chloride.
Brown teaches “[m]agnetic surfactant” (Title). Brown further teaches that “[s]urfactants are ubiquitous, being important commodity chemicals with wide industrial applications, and essential components of living organisms. With stimuli-responsive surfactants, self-assembly and physicochemical properties of a wide variety of materials may be readily manipulated, both reversibly and irreversibly” (Abstract). Brown further teaches that surfactants “also generate self-assembled structures in solution over nanometer to micron length scales; these structures include micelles…and affect physicochemical and optoelectronic properties” (page 140 column 1 paragraph 1). Brown further suggests contacting a non-ionic surfactant with an iron salt said iron salt being iron chloride (“This may also be the case for the surfactant iron chloride mixtures studied by these authors, as, perhaps unexpectedly, ferric ions interact even with non-ionic surfactants such as Brij making them magnetic” page 141 column 1 paragraph 2). Brown suggests that adding an iron chloride to the non-ionic detergent enables magnetic surfactants which can be an alternative to magnetic nanoparticles for the effective control and manipulation of biomolecules, including protein separations (“a large variety of magnetic ionic liquids (MILs) have been generated with iron… nanoparticle-free MILs are themselves paramagnetic and have opened up many new research areas of interest, including fluid–fluid separations and chemical reactions [28]. Because MILs are non-volatile, they offer advantages over conventional ferrofluids, which often employ flammable organic solvents” page 141 column 1 paragraph 2 “2.3. Control and manipulation of biomolecules… In the field of biotechnology, the effective control over the transport and delivery of biomolecules is still a major challenge but is vital for protein separations… magnetic nanoparticles have provided most of the solutions and been used with some success [47,48]. However, there are often many drawbacks to their efficient employment, such as bioreactivity, toxicity, and sedimentation [49]. In addition, the synthesis of ultrafine particles can also be challenging, and the ensuing interactions between the particle surface and the biomolecules may disrupt native form and function. Using magnetic surfactants could offer significant advantages in this respect, due to facile synthesis, effective binding, and good dispersibility in solution” page 142 column 2 paragraph 2). Brown further teaches that “[i]t was demonstrated that these new MILSs behave like conventional surfactants in that they form micelles” (page 141 column 2 paragraph 3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Patchornik to rely on the iron salt being iron chloride taught by Brown because Brown suggests that this generates magnetic surfactants, which enable effective manipulation of biomolecules for protein separation and Patchornik is concerned with isolating antibodies, i.e. separating proteins. A person having ordinary skill in the art would have had a reasonable expectation of success because Brown teaches the combination of non-ionic surfactant and iron chloride and suggests that this generates a micelle capable of effectively manipulating and isolating a protein, and Patchornik teaches engineered micelles comprising a non-ionic surfactant and an iron salt for antibody isolation.
Regarding claim 2, Patchornik in view of Brown teach the method of claim 1 as discussed above.
Patchornik further suggests further comprising filtering said medium comprising said aggregate (Fig. 5B, “Depending on the intended use of the antibody that is isolated and optionally solubilized, the protein (either membrane or cytosolic) or agent that is bound thereto, may be subjected to further purification steps. This may be effected by using a number of biochemical methods which are well known in the art” page 18 lines 30-33, “Examples of additional purification steps (and the order they may be carried out) are summarized in Figure 5B” page 19 lines 6-7, see Fig. 5B showing the chromatographic filtration steps). Note that although Patchornik fails to use the language “further comprising filtering said medium”, the teaching of applying two chromatographic steps inherently provides a further step of filtering said medium comprising said aggregate.
Regarding claim 11, Patchornik in view of Brown teach the method of claim 1 as discussed above.
Patchornik further suggests wherein said medium comprises a cell lysate (“The method of claim 1, wherein said medium comprises a cell lysate” claim 4).
Regarding claim 14, Patchornik in view of Brown teach the method of claim 1 as discussed above.
Patchornik further suggests wherein said medium comprises serum albumin (“The method of claim 1 or 6, wherein said medium comprises serum albumin” claim 7).
Regarding claim 16, Patchornik in view of Brown teach the method of claim 1 as discussed above.
Patchornik further suggests wherein said conditions of step (b) comprise having a level of salt between 20-100 mM (“The concentration of salt (e.g. NaCl) in the aggregates is typically, below 100 mM and more preferably below 50 mM… Exemplary ranges include 20-100 mM” page 17 lines 16-19, page 24 lines 15-19).
Regarding claim 17, Patchornik in view of Brown teach the method of claim 1 as discussed above.
Patchornik further suggests further comprising solubilizing said antibody following step (b) (“The method of claim 1, further comprising solubilizing said antibody following step (b)” claim 10).
Regarding claims 19-20, Patchornik in view of Brown teach the method of claim 1 as discussed above.
Patchornik further suggests wherein said solubilizing is effected with a buffer having a pH between 3.8 and 4 wherein said buffer is sodium acetate (Applicant’s elected species) (“Extraction may be effected with a buffer having a pH between 3-6, and more preferably between 3.8-5. In one embodiment, the buffer is a carboxylic buffer, examples of which include, but are not limited to sodium acetate” page 18 lines 5-7). With regards to the claimed range of pH 3.8-4, the prior art teaches a range of 3.8-5. In such a case, since there is a substantial overlap of the claimed range and the prior art range, a prima facie case of obviousness exists because it would have been obvious to a person having ordinary skill in the art to arrive at the claimed range by selecting values disclosed within the prior art range. See MPEP 2144.05.
Regarding claim 29, Patchornik in view of Brown teach the method of claim 1 as discussed above.
Patchornik further suggests wherein said polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80 (“the polysorbate surfactant is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80” page 3 lines 7-8, “Tween-20” page 24 lines 15-19).
New Rejections
Claim(s) 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Patchornik et al. (WO 2018/207184 A2) (Cite No. 5 of IDS filed 4/6/2022) (“Patchornik”) in view of Wang et al. Journal of Immunological Methods 314 (2006) 1–8 doi:10.1016/j.jim.2006.05.002 (“Wang”).
The rejection of claim 4 is new, necessitated by the amendments.
Regarding claim 4, Patchornik teaches a method of isolating an antibody (Title, Fig. 1), the method comprising: (a) contacting bathophenanthroline, a non-ionic detergent and iron ions so as to generate an aggregate comprising said bathophenanthroline, said detergent and said iron ions (Abstract, page 24 lines 15-19); (b) contacting said aggregate with a medium comprising the antibody under conditions that allow partitioning of the antibody into said aggregate (“and contacting the aggregate with a medium comprising the antibody under conditions that allow partitioning of the antibody into the aggregate” Abstract); and subsequently (d) releasing the antibody from said aggregate (“Pellets were dissolved in the presence of sample buffer and analyzed by SDS-PAGE” page 24 line 24), wherein said non-ionic detergent is a polysorbate, a polyoxyethylene oleyl ether or octylphenol ethoxylate, thereby isolating the antibody (“90 μL of 0.25 mM Tween-20” page 24 lines 15-19).
Patchornik fails to teach step (c) filtering said medium comprising said aggregate.
Wang teaches “[p]urification of humanized monoclonal antibodies by membrane-based hybrid bioseparation technique” (Title). Wang further teaches contacting a salt with a medium comprising antibodies, thereby forming aggregates of antibodies that precipitate from the medium (“The principle of the hybrid bioseparation technique is shown in Fig. 1, this being cyclic in nature i.e. of the capture and release type. A fraction of the mAb in a feed sample is precipitated using high ammonium sulphate concentration” page 2 col. 2 para. 2). Wang further teaches filtering the medium comprising said aggregates and subsequently releasing the antibody from said aggregate (“this is retained by sieving using a microfiltration membrane… The retained mAb is subsequently released by reducing the ammonium sulphate concentration which results in the simultaneous dissolution of the precipitated mAb” page 2 col. 2 para. 2, see Figure 1 showing the filtering of the aggregates). Wang further suggests that filtering and subsequently releasing the antibody from said aggregate yields high antibody purity and recoveries (“The monoclonal antibody purities and recoveries obtained in the experiments described in this paper were very high” Abstract). Furthermore, Wang teaches that the filtration is facile and accessible (“This technique uses standard laboratory reagents such as ammonium sulphate and of-the-shelf microfiltration membranes and is significantly less expensive than techniques such as protein-A or protein-G based affinity chromatography…. Therefore similar separations could easily be carried out in a facile manner in the laboratory using syringes for pushing appropriate volumes of capture, feed and release solutions sequentially through the syringe filter holder” page 7 col. 2 paras. 1-2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Patchornik to include the step (c) filtering said medium comprising said aggregate taught by Wang because Wang suggests this enables high antibody recoveries and purity and Patchornik is interested in methods of isolating and purifying antibodies. Furthermore a person having ordinary skill in the art would have found it obvious to apply the art recognized technique of filtration taught by Wang to the base method of forming antibody aggregates for isolation and purification taught by both Patchornik and Wang. A person having ordinary skill in the art would have had a reasonable expectation of success because Wang suggests that a filtration step is facile and accessible.
Maintained Rejections
Claims 5-8 and 18 are rejected under 35 U.S.C. 103(a) as being unpatentable over Patchornik in view of Kumar et al. BIOTECHNOLOGY AND BIOENGINEERING, VOL. 84, NO. 4, NOVEMBER 20, 2003 (Cite No. 28 of IDS 4/6/2022) (“Kumar”) and Dutta Analyst, 2015, 140, 204 (Cite No. 2 of IDS 7/11/2023).
Regarding claims 5-7 and 18, Patchornik teaches a method of preparing an aggregate, the method comprising: (a) contacting bathophenanthroline, a non-ionic detergent and metal ions so as to generate an aggregate comprising said bathophenanthroline, wherein said non-ionic detergent is a polysorbate, a polyoxyethylene oleyl ether or octylphenol ethoxylate and wherein said metal ions comprise iron ions , said detergent and said metal ions (“Preparation of Tween-20 aggregates” page 24 lines 15-19); and (b) contacting said aggregate with a medium comprising an antibody under conditions that allow a first fraction of said antibody to partition into said aggregate (Abstract); (c) isolating said antibody from said aggregate (Abstract). Note that although Patchornik fails to use the language “a first fraction of said antibody to partition into said aggregate”, the teaching of the antibody partition into said aggregate inherently provides a first fraction of said antibody to partition into said aggregate, that is because an antibody inherently contains fractions of itself. Note that the claim is not limited to the antibody being a fragment (or fraction) of itself.
Patchornik fails to teach instantly claimed steps (d)-(f), wherein said disassociating said aggregate comprises contacting said aggregate with a water soluble chelator under conditions that allow dissociation of said aggregate, wherein said water soluble chelator comprises EDTA or EGTA, wherein said isolating said antibody comprises solubilizing said antibody.
Kumar teaches “a detailed study of a new purification system using metal-loaded thermoresponsive copolymers as [metal affinity macroligands] AML. … When loaded with Cu(II) and Ni(II) ions the copolymers selectively precipitated extracellularly expressed histidine-tagged single-chain Fv-antibody fragments (His6-scFv fragments) from the fermentation broth free from E. coli cells” (Abstract). Kumar further suggests step (c) isolating said antibody from said aggregate and (d) disassociating said aggregate, wherein said disassociating said aggregate comprises contacting said aggregate with a water soluble chelator under conditions that allow dissociation of said aggregate, wherein said water soluble chelator is EDTA and wherein said isolating said antibody comprises solubilizing said antibody (“The target antibody fragments were dissociated from the polymer by dissolving the polymer-protein pellet in 0.5 mL 50 mM EDTA buffer, pH 8, containing 50 mM NaCl while the mixture was kept on ice” page 496 col. 2 para. 2). Note that Kumar teaches both step (c) and step (d) using EDTA to dissolve the aggregate, i.e. solubilize the antibody and disassociate the aggregate. Kumar further suggests (e) isolating said bathophenanthroline; and subsequently (f) contacting said bathophenanthroline, a non-ionic detergent and metal ions so as to generate a second aggregate comprising said bathophenanthroline, said detergent and said metal ions, thereby preparing the aggregate (“Finally, the desired protein is dissociated from the AML and the latter can be recovered and reused in further cycles” page 495 col. 1 para. 2). Note that although Kumar fails to explicitly teach bathophenanthroline, the reagent used by Kumar, i.e. the metal affinity macroligands, would inherently suggest to a person having ordinary skill in the art its application as the bathophenanthroline and subsequent isolation (step (e)) and contacting (step (f)) in the instant method of preparing an aggregate because it is a functional equivalent to the bathophenanthroline (the metal affinity macroligands also serve to form aggregates comprising metal ions for partitioning of an antibody (see Abstract of Kumar)).
Dutta teaches “[e]ngineered-membranes and engineered-micelles as efficient tools for purification of halorhodopsin and bacteriorhodopsin” (Title). Dutta teaches steps (a)-(c) but drawn to isolating a membrane protein (“engineered-micelles. These are specifically conjugated in the presence of [hydrophobic chelator:Fe2+]complexes and form detergent aggregates into which membrane proteins partition, but hydrophilic water-soluble proteins do not. The approach was tested on…five non-ionic detergents (OG, OTG, NG, DM, and DDM), commonly used in purification and crystallization of membrane proteins, in combination with the commercially available bathophenanthroline or with one of the three synthesized phenanthroline derivatives (Phen-C10, Phen-C8 and Phen-C6). Our results show that bR is extracted efficiently (60–86%) and directly from its native membrane into diverse detergent aggregates with preservation of its native conformation, while 90–95% of an artificial contaminating background is excluded” Abstract). Dutta further teaches that “[e]fficient pellet dissolution was observed in the presence of EDTA (50 mM) and imidazole (200 mM)” (page 205 col. 2 para. 4).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Patchornik to include instantly claimed steps (d)-(f), wherein said disassociating said aggregate comprises contacting said aggregate with a water soluble chelator under conditions that allow dissociation of said aggregate, wherein said water soluble chelator comprises EDTA, and wherein said isolating said antibody comprises solubilizing said antibody taught by Kumar because Kumar suggests that this enables the reuse of the bathophenanthroline multiple times and Patchornik relies on bathophenanthroline. A person having ordinary skill in the art would have had a reasonable expectation of success because Dutta teaches that EDTA is capable of efficiently disassociating said aggregate comprising the bathophenanthroline. Furthermore, both Patchornik, Kumar and Dutta teach methods related to preparing an aggregate.
Regarding claim 8, Patchornik in view of Kumar and Dutta teach the method of claim 5 as discussed above.
Patchornik further suggests wherein said isolating said antibody from said aggregate comprises filtering said medium comprising said aggregate (Fig. 5B, page 29 lines 3-4 and 32-34).
Claims 26-27 are rejected under 35 U.S.C. 103(a) as being unpatentable over Patchornik as applied to claim 25 above and further in view of Dutta.
Regarding claims 26-27, Patchornik teaches the method of claim 25 as discussed above.
Patchornik fails to teach wherein said conditions comprise a pH of between 5-9, wherein said pH is between 7-8.
Kumar teaches “a detailed study of a new purification system using metal-loaded thermoresponsive copolymers as [metal affinity macroligands] AML. … When loaded with Cu(II) and Ni(II) ions the copolymers selectively precipitated extracellularly expressed histidine-tagged single-chain Fv-antibody fragments (His6-scFv fragments) from the fermentation broth free from E. coli cells” (Abstract). Kumar further teaches wherein said conditions comprise a pH of between 5-9, wherein said pH is between 7-8 (“The cell supernatant (5 mL) was dialyzed against distilled water (4 L) for 3 h to remove the sodium azide-benzamidine preservative. The samples were briefly kept on ice (to prevent polymer precipitation) before the pH was adjusted to 7. The polymer-protein mixture was allowed to incubate at room temperature for 30 min during mixing on a rotating shaker “page 496 col. 2 para. 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Patchornik to rely on the pH being between 7-8 taught by Kumar because Kumar suggests that this enables the isolation of antibodies from cell supernatant (using physiological pH) and Patchornik is concerned with methods of isolating antibodies. A person having ordinary skill in the art would have had a reasonable expectation of success because both Patchornik and Kumar teach methods drawn to isolating an antibody fragment using aggregates comprising a metal ions wherein the antibody partitions into the aggregate.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
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.
U.S. Patent No. 12091445 B2
Claims 1, 3, 11, 16-17, 19-20 and 29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12091445 B2 in view of Brown.
Regarding claims 1, 3, 11 and 16, U.S. Patent No. 12091445 B2 recites a method of isolating an antibody, the method comprising: (a) contacting bathophenanthroline, a non-ionic detergent and iron ions, so as to generate an aggregate comprising said bathophenanthroline, said detergent and said iron ions, said non-ionic detergent being a polysorbate, a polyoxyethylene oleyl ether or octylphenol ethoxylate; and (b) contacting said aggregate with a medium comprising the antibody under conditions that allow partitioning of the antibody into said aggregate, thereby isolating the antibody (claim 1) wherein said conditions of step (b) comprise having a level of salt between 20-100 mM (claim 4), wherein said medium comprises a cell lysate (claim 2).
U.S. Patent No. 12091445 B2 fails to recite iron salt, wherein the iron salt is iron chloride.
Brown teaches “[m]agnetic surfactant” (Title). Brown further teaches that “[s]urfactants are ubiquitous, being important commodity chemicals with wide industrial applications, and essential components of living organisms. With stimuli-responsive surfactants, self-assembly and physicochemical properties of a wide variety of materials may be readily manipulated, both reversibly and irreversibly” (Abstract). Brown further teaches that surfactants “also generate self-assembled structures in solution over nanometer to micron length scales; these structures include micelles…and affect physicochemical and optoelectronic properties” (page 140 column 1 paragraph 1). Brown further suggests contacting a non-ionic surfactant with an iron salt said iron salt being iron chloride (page 141 column 1 paragraph 2). Brown suggests that adding an iron chloride to the non-ionic detergent enables magnetic surfactants which can be an alternative to magnetic nanoparticles for the effective control and manipulation of biomolecules, including protein separations (page 141 column 1 paragraph 2, page 142 column 2 paragraph 2). Brown further teaches that “[i]t was demonstrated that these new MILSs behave like conventional surfactants in that they form micelles” (page 141 column 2 paragraph 3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12091445 B2 to rely on the iron ions being from an iron salt, the iron salt being iron chloride taught by Brown because Brown suggests that this generates magnetic surfactants, which enable effective manipulation of biomolecules for protein separation and U.S. Patent No. 12091445 B2 is concerned with isolation of antibodies. A person having ordinary skill in the art would have had a reasonable expectation of success because Brown teaches the combination of non-ionic surfactant and iron chloride and suggests that this generates a micelle capable of effectively manipulating and isolating a protein, and U.S. Patent No. 12091445 B2 recites aggregates comprising a non-ionic surfactant and iron ions for antibody isolation.
Regarding claims 17 and 20, U.S. Patent No. 12091445 B2 in view of Brown address claim 1 as discussed above.
U.S. Patent No. 12091445 B2 further recites, further comprising solubilizing said antibody following step (b) (claim 5), wherein said solubilizing is effected with a buffer having a pH between 3.8 and 4 (claim 7).
Regarding claim 19, U.S. Patent No. 12091445 B2 in view of Brown address claim 1 as discussed above.
U.S. Patent No. 12091445 B2 further recites wherein said solubilizing is effected with a buffer having a pH between 3-6 wherein said buffer: (i) further comprises a salt; (ii) is sodium acetate; or (iii) comprises an amino acid selected from the group consisting of isoleucine, valine, and glycine (claims 8-11).
Regarding claim 29, U.S. Patent No. 12091445 B2 in view of Brown address claim 1 as discussed above.
U.S. Patent No. 12091445 B2 further recites wherein said polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80 (claims 12-13).
Claims 2 and 14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12091445 B2 in view of Brown as discussed above, and further in view of Patchornik.
Regarding claim 2, U.S. Patent No. 12091445 B2 in view of Brown address the method of claim 1 as discussed above.
U.S. Patent No. 12091445 B2 in view of Brown fail to recite further comprising filtering said medium comprising said aggregate.
Patchornik teaches a method of isolating an antibody (Title, Fig. 1), the method comprising: (a) contacting bathophenanthroline, a non-ionic detergent and an iron salt, so as to generate an aggregate comprising said bathophenanthroline, said detergent and iron ions of said iron salt, said non-ionic detergent being a polysorbate, a polyoxyethylene oleyl ether or octylphenol ethoxylate (page 24 lines 15-19); and (b) contacting said aggregate with a medium comprising the antibody under conditions that allow partitioning of the antibody into said aggregate, thereby isolating the antibody (Abstract). Patchornik further suggests further comprising filtering said medium comprising said aggregate (Fig. 5B, page 29 lines 3-4 and 32-34). Patchornik suggests that this enables the removal/exclusion of impurities (“In certain embodiments of the present invention, a diafiltration step is employed to exchange the various buffers used in connection with the instant invention, optionally prior to further chromatography or other purification steps, as well as to remove impurities from the antibody” page 20 lines 27-30).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12091445 B2 to rely on the filtering of said medium comprising said aggregate taught by Patchornik because Patchornik suggests that this enables the removal/exclusion of impurities. A person having ordinary skill in the art would have had a reasonable expectation of success because both Patchornik and U.S. Patent No. 12091445 B2 teach a method of isolating an antibody, the method comprising: (a) contacting bathophenanthroline, a non-ionic detergent and iron ions, so as to generate an aggregate comprising said bathophenanthroline, said detergent and said iron ions; and (b) contacting said aggregate with a medium comprising the antibody under conditions that allow partitioning of the antibody into said aggregate, thereby isolating the antibody.
Regarding claim 14, U.S. Patent No. 12091445 B2 in view of Brown address the method of claim 1 as discussed above.
U.S. Patent No. 12091445 B2 in view of Brown fail to recite wherein said medium comprises serum albumin.
Patchornik further suggests wherein said medium comprises serum albumin (“The method of claim 1 or 6, wherein said medium comprises serum albumin” claim 7).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12091445 B2 to rely on said medium comprising serum albumin taught by Patchornik because it would be a simple matter of applying a known technique to a known method. In this case, both U.S. Patent No. 12091445 B2 and Patchornik teach a method of isolating an antibody, the method comprising: (a) contacting bathophenanthroline, iron ions and polysorbate so as to generate an aggregate and (b) contacting said aggregate with a medium comprising the antibody. Patchornik simply applies the art recognized technique of the medium comprising serum albumin. Therefore, a person having ordinary skill in the art would have found it obvious to apply the technique of Patchornik to the base method taught by both Patchornik and U.S. Patent No. 12091445 B2. A person having ordinary skill in the art would have had a reasonable expectation of success because both Patchornik and U.S. Patent No. 12091445 B2 teach a method of isolating an antibody, the method comprising: (a) contacting bathophenanthroline, a non-ionic detergent and iron ions, so as to generate an aggregate comprising said bathophenanthroline, said detergent and said iron ions; and (b) contacting said aggregate with a medium comprising the antibody under conditions that allow partitioning of the antibody into said aggregate, thereby isolating the antibody.
New Rejection
Claim 4 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12091445 B2 in view of Wang.
Regarding claim 4, U.S. Patent No. 12091445 B2 recites steps (a)-(b) and subsequent (d) releasing the antibody from said aggregate, wherein said non-ionic detergent is a polysorbate, a polyoxyethylene oleyl ether or octylphenol ethoxylate (claims 1, 5 and 13).
U.S. Patent No. 12091445 B2 fails to recite step (c).
Wang teaches “[p]urification of humanized monoclonal antibodies by membrane-based hybrid bioseparation technique” (Title). Wang further teaches contacting a salt with a medium comprising antibodies, thereby forming aggregates of antibodies that precipitate from the medium (page 2 col. 2 para. 2). Wang further teaches filtering the medium comprising said aggregates and subsequently releasing the antibody from said aggregate (page 2 col. 2 para. 2, see Figure 1 showing the filtering of the aggregates). Wang further suggests that filtering and subsequently releasing the antibody from said aggregate yields high antibody purity and recoveries (Abstract). Furthermore, Wang teaches that the filtration is facile and accessible (page 7 col. 2 paras. 1-2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12091445 B2 to include the step (c) filtering said medium comprising said aggregate taught by Wang because Wang suggests this enables high antibody recoveries and purity and U.S. Patent No. 12091445 B2 is interested in methods of purifying antibodies. Furthermore a person having ordinary skill in the art would have found it obvious to apply the art recognized technique of filtration taught by Wang to the base method of forming antibody aggregates for isolation and purification taught by both U.S. Patent No. 12091445 B2 and Wang. A person having ordinary skill in the art would have had a reasonable expectation of success because Wang suggests that the filtration is facile and accessible.
Claims 5-7 and 18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12091445 B2 in view of Kumar and Dutta.
Regarding claims 5-7 and 18, U.S. Patent No. 12091445 B2 recites steps (a)-(c) (claim 1).
U.S. Patent No. 12091445 B2 fails to recite steps (d)-(f), wherein said disassociating said aggregate comprises contacting said aggregate with a water soluble chelator under conditions that allow dissociation of said aggregate, wherein said water soluble chelator comprises EDTA or EGTA, wherein said isolating said antibody comprises solubilizing said antibody.
Kumar teaches “a detailed study of a new purification system using metal-loaded thermoresponsive copolymers as [metal affinity macroligands] AML. … When loaded with Cu(II) and Ni(II) ions the copolymers selectively precipitated extracellularly expressed histidine-tagged single-chain Fv-antibody fragments (His6-scFv fragments) from the fermentation broth free from E. coli cells” (Abstract). Kumar further suggests step (c) isolating said antibody from said aggregate and (d) disassociating said aggregate, wherein said disassociating said aggregate comprises contacting said aggregate with a water soluble chelator under conditions that allow dissociation of said aggregate, wherein said water soluble chelator is EDTA and wherein said isolating said antibody comprises solubilizing said antibody (page 496 col. 2 para. 2). Note that Kumar teaches both step (c) and step (d) using EDTA to dissolve the aggregate, i.e. solubilize the antibody and disassociate the aggregate. Kumar further suggests (e) isolating said bathophenanthroline; and subsequently (f) contacting said bathophenanthroline, a non-ionic detergent and metal ions so as to generate a second aggregate comprising said bathophenanthroline, said detergent and said metal ions, thereby preparing the aggregate (page 495 col. 1 para. 2). Note that although Kumar fails to teach a bathophenanthroline, the reagent used by Kumar, i.e. the metal affinity macroligands, would inherently suggest to a person having ordinary skill in the art its application as the bathophenanthroline and subsequent isolation (step (e)) and contacting (step (f)) in the instant method of preparing an aggregate because it is a functional equivalent to the bathophenanthroline (the metal affinity macroligands also serve to form aggregates comprising metal ions for partitioning of an antibody (see Abstract of Kumar)).
Dutta teaches “[e]ngineered-membranes and engineered-micelles as efficient tools for purification of halorhodopsin and bacteriorhodopsin” (Title). Dutta teaches steps (a)-(c) but drawn to isolating a membrane protein (Abstract). Dutta further teaches that “[e]fficient pellet dissolution was observed in the presence of EDTA (50 mM) and imidazole (200 mM)” (page 205 col. 2 para. 4).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12091445 B2 to rely on the steps (d)-(f), wherein said disassociating said aggregate comprises contacting said aggregate with a water soluble chelator under conditions that allow dissociation of said aggregate, wherein said water soluble chelator comprises EDTA, and wherein said isolating said antibody comprises solubilizing said antibody taught by Kumar because Kumar suggests that this enables the reuse of the bathophenanthroline multiple times and of U.S. Patent No. 12091445 B2 relies on bathophenanthroline. A person having ordinary skill in the art would have had a reasonable expectation of success because Dutta teaches that EDTA is capable of efficiently disassociating said aggregate comprising the bathophenanthroline. Furthermore, both U.S. Patent No. 12091445 B2, Kumar and Dutta teach methods related to preparing an aggregate.
Claim 8 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12091445 B2 in view of Kumar and Dutta as applied to claim 5 above, and further in view of Patchornik.
U.S. Patent No. 12091445 B2 in view of Kumar and Dutta fail to recite wherein said isolating said antibody from said aggregate comprises filtering said medium comprising said aggregate.
Patchornik further suggests wherein said isolating said antibody from said aggregate comprises filtering said medium comprising said aggregate (Figure 5B, page 29 lines 3-4 and 32-34). Patchornik suggests that this enables the removal/exclusion of impurities (page 20 lines 27-30).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12091445 B2 to rely on the filtering of said medium comprising said aggregate taught by Patchornik because Patchornik suggests that this enables the removal/exclusion of impurities. A person having ordinary skill in the art would have had a reasonable expectation of success because both Patchornik and U.S. Patent No. 12091445 B2 teach a method of isolating an antibody, the method comprising: (a) contacting bathophenanthroline, a non-ionic detergent and iron ions, so as to generate an aggregate comprising said bathophenanthroline, said detergent and said iron ions; and (b) contacting said aggregate with a medium comprising the antibody under conditions that allow partitioning of the antibody into said aggregate, thereby isolating the antibody.
Claim 25 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12091445 B2 in view of Patchornik.
Regarding claim 25, U.S. Patent No. 12091445 B2 recites steps (a)-(c) but drawn to an antibody, not a fragment thereof.
U.S. Patent No. 12091445 B2 fails to recite antibody fragment.
Patchornik teaches a method of isolating an antibody fragment of interest (Title, Fig. 1, Abstract, page 9 lines 9-10) comprising: (a) contacting bathophenanthroline, a non-ionic detergent and iron ions so as to generate an aggregate comprising said bathophenanthroline, said detergent and said iron ions, wherein said non-ionic detergent is a polysorbate, a polyoxyethylene oleyl ether or octylphenol ethoxylate (Abstract, page 24 lines 15-19); (b) contacting said aggregate with a medium comprising: (i) an antibody fragment which comprises an Fc region and is devoid of an antigen binding region; and (ii) an antibody fragment which is devoid of an Fc region (page 11 lines 4 and 9-10) wherein said contacting is effected under conditions such that the antibody fragment which comprises an Fc region partitions preferentially into said aggregate relative to the antibody fragment which comprises an antigen binding region, so as to generate an antibody fragment-enriched aggregate and an antibody fragment-enriched medium; and (c) isolating said antibody fragment of interest from said fragment-enriched aggregate or from said fragment-enriched medium, thereby isolating the antibody fragment of interest (Abstract, page 24 lines 15-19).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12091445 B2 to rely on the method being drawn to antibody fragments as taught by Patchornik because it would have been a simple matter of applying a known technique to a known method. In this case, both U.S. Patent No. 12091445 B2 and Patchornik teach the base method of isolating an antibody. Patchornik simply applies the art-recognized technique of using the method for isolating antibody fragments. Therefore, a person having ordinary skill in the art would have found it obvious to apply the technique taught by Patchornik to the meth taught by both references. A person having ordinary skill in the art would have had a reasonable expectation of success because both Patchornik and U.S. Patent No. 12091445 B2 teach a method of isolating an antibody, the method comprising: (a) contacting a bathophenanthroline, a non-ionic detergent and iron ions, so as to generate an aggregate comprising said bathophenanthroline, said detergent and said iron ions; and (b) contacting said aggregate with a medium comprising the antibody thereby isolating the antibody.
Claims 26-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12091445 B2 in view of Patchornik as applied to claim 25 above, and further in view of Dutta.
Regarding claims 26-27, U.S. Patent No. 12091445 B2 in view of Patchornik recite the method of claim 25 as discussed above.
U.S. Patent No. 12091445 B2 in view of Patchornik fail to recite wherein said conditions comprise a pH of between 5-9, wherein said pH is between 7-8.
Kumar teaches “a detailed study of a new purification system using metal-loaded thermoresponsive copolymers as [metal affinity macroligands] AML. … When loaded with Cu(II) and Ni(II) ions the copolymers selectively precipitated extracellularly expressed histidine-tagged single-chain Fv-antibody fragments (His6-scFv fragments) from the fermentation broth free from E. coli cells” (Abstract). Kumar further teaches wherein said conditions comprise a pH of between 5-9, wherein said pH is between 7-8 (page 496 col. 2 para. 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12091445 B2 in view of Patchornik to rely on the pH being between 7-8 taught by Kumar because Kumar suggests that this enables the isolation of antibodies from cell supernatant (using physiological pH) and U.S. Patent No. 12091445 B2 in view of Patchornik are concerned with methods of isolating antibodies. A person having ordinary skill in the art would have had a reasonable expectation of success because both U.S. Patent No. 12091445 B2 in view of Patchornik and Kumar teach methods drawn to isolating an antibody fragment using aggregates comprising a metal ions wherein the antibody partitions into the aggregate.
U.S. Patent No. 12454567 B2
Claims 1, 3, 14, 16-17 and 19-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12454567 B2.
Regarding claims 1, 3 and 14, U.S. Patent No. 12454567 B2 recites a method of isolating an antibody, the method comprising: (a) contacting bathophenanthroline, a non-ionic detergent and an iron salt, so as to generate an aggregate comprising said bathophenanthroline, said detergent and iron ions of said iron salt, said iron salt being iron chloride said non-ionic detergent being a polysorbate, a polyoxyethylene oleyl ether or octylphenol ethoxylate; and (b) contacting said aggregate with a medium comprising the antibody under conditions that allow partitioning of the antibody into said aggregate, thereby isolating the antibody, (claims 1 and 11), wherein said medium comprises serum albumin (claim 6).
Regarding claim 16, U.S. Patent No. 12454567 B2 recites wherein said conditions of step (b) comprise having a level of salt between 20-100 mM (claim 7).
Regarding claims 17 and 19-20, U.S. Patent No. 12454567 B2 recites further comprising solubilizing said antibody following step (b) (claim 8), wherein said solubilizing is effected with a buffer having a pH between 3-6 wherein said buffer:(i) further comprises a salt;(ii) is a carboxylic buffer; or(iii) comprises an amino acid, wherein said solubilizing is effected with a buffer having a pH between 3.8 and 4 (claim 9), wherein said buffer is sodium acetate (claim 10).
Claims 2, 11 and 29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12454567 B2 as applied to claim 1 above and further in view of Patchornik.
Regarding claim 2, U.S. Patent No. 12454567 B2 recites the method of claim 1 as discussed above.
U.S. Patent No. 12454567 B2 fails to recite further comprising filtering said medium comprising said aggregate.
Patchornik teaches a method of isolating an antibody (Title, Fig. 1), the method comprising: (a) contacting bathophenanthroline, a non-ionic detergent and an iron salt, so as to generate an aggregate comprising said bathophenanthroline, said detergent and iron ions of said iron salt, said non-ionic detergent being a polysorbate, a polyoxyethylene oleyl ether or octylphenol ethoxylate (page 24 lines 15-19); and (b) contacting said aggregate with a medium comprising the antibody under conditions that allow partitioning of the antibody into said aggregate, thereby isolating the antibody (Abstract). Patchornik further suggests further comprising filtering said medium comprising said aggregate (Fig. 5B, page 29 lines 3-4 and 32-34). Patchornik suggests that this enables the removal/exclusion of impurities (page 20 lines 27-30).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12454567 B2 to rely on the filtering of said medium comprising said aggregate taught by Patchornik because Patchornik suggests that this enables the removal/exclusion of impurities. A person having ordinary skill in the art would have had a reasonable expectation of success because both Patchornik and U.S. Patent No. 12454567 B2 teach a method of isolating an antibody, the method comprising: (a) contacting bathophenanthroline, a non-ionic detergent and iron ions, so as to generate an aggregate comprising said bathophenanthroline, said detergent and said iron ions; and (b) contacting said aggregate with a medium comprising the antibody under conditions that allow partitioning of the antibody into said aggregate, thereby isolating the antibody.
Regarding claim 11, U.S. Patent No. 12454567 B2 recites the method of claim 1 as discussed above.
U.S. Patent No. 12454567 B2 fails to recite wherein said medium comprises a cell lysate.
Patchornik further teaches wherein said medium comprises a cell lysate (claim 4). Patchornik further teaches that “[t]o demonstrate IgG purification, a mixture of a target human IgG in E. coli lysate (which served as an artificial contamination background) was added to preformed Tween-20 aggregates” (page 7 lines 31-32).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12454567 B2 to rely on the medium comprising a cell lysate taught by Patchornik because it would have been a simple matter of applying a known technique to a known method. In this case both U.S. Patent No. 12454567 B2 and Patchornik teach the method of isolating an antibody as recited in claim 1. Patchornik simply included a cell lysate in the medium. Therefore, a person having ordinary skill in the art would have found it obvious to apply the teachings of Patchornik to the base method taught by both references. Furthermore, Patchornik teaches that cell lysates can also serve as an artificial contamination background. A person having ordinary skill in the art would have had a reasonable expectation of success because both Patchornik and U.S. Patent No. 12454567 B2 teach a method of isolating an antibody, the method comprising: (a) contacting bathophenanthroline, a non-ionic detergent and iron ions, so as to generate an aggregate comprising said bathophenanthroline, said detergent and said iron ions; and (b) contacting said aggregate with a medium comprising the antibody under conditions that allow partitioning of the antibody into said aggregate, thereby isolating the antibody.
Regarding claim 29, U.S. Patent No. 12454567 B2 recites the method of claim 1 as discussed above.
U.S. Patent No. 12454567 B2 fails to recite wherein said polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80.
Patchornik further suggests wherein said polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80 (“the polysorbate surfactant is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80” page 3 lines 7-8, “Tween-20” page 24 lines 15-19).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12454567 B2 to rely on the polysorbate being polysorbate 20 taught by Patchornik for the same reasons as above, i.e. it would have been a simple matter of applying a known technique to a known base method. A person having ordinary skill in the art would have had a reasonable expectation of success because both Patchornik and U.S. Patent No. 12454567 B2 teach a method of isolating an antibody.
New Rejection
Claim 4 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12454567 B2 in view of Wang.
Regarding claim 4, U.S. Patent No. 12454567 B2 recites steps (a)-(b) (claims 1 and 11).
U.S. Patent No. 12454567 B2 fails to recite step (c).
Wang teaches “[p]urification of humanized monoclonal antibodies by membrane-based hybrid bioseparation technique” (Title). Wang further teaches contacting a salt with a medium comprising antibodies, thereby forming aggregates of antibodies that precipitate from the medium (page 2 col. 2 para. 2). Wang further teaches filtering the medium comprising said aggregates and subsequently releasing the antibody from said aggregate (page 2 col. 2 para. 2, see Figure 1). Wang further suggests that filtering and subsequently releasing the antibody from said aggregate yields high antibody purity and recoveries (Abstract). Furthermore, Wang teaches that the filtration is facile and accessible (page 7 col. 2 paras. 1-2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12454567 B2 to include the step (c) filtering said medium comprising said aggregate taught by Wang because Wang suggests this enables high antibody recoveries and purity and U.S. Patent No. 12454567 B2 is interested in methods of purifying antibodies. A person having ordinary skill in the art would have had a reasonable expectation of success because both U.S. Patent No. 12454567 B2 and Wang teach the formation of aggregates comprising antibodies, and their subsequent release from the aggregate for isolating antibodies. Furthermore, Wang suggests that the filtration is facile and accessible.
Claims 5-7 and 18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12454567 B2 in view of Kumar and Dutta.
Regarding claims 5-7 and 18, U.S. Patent No. 12454567 B2 recites steps (a)-(c) (claims 1 and 11).
U.S. Patent No. 12454567 B2 fails to recite steps (d)-(f), wherein said disassociating said aggregate comprises contacting said aggregate with a water soluble chelator under conditions that allow dissociation of said aggregate, wherein said water soluble chelator comprises EDTA or EGTA, wherein said isolating said antibody comprises solubilizing said antibody.
Kumar teaches “a detailed study of a new purification system using metal-loaded thermoresponsive copolymers as [metal affinity macroligands] AML. … When loaded with Cu(II) and Ni(II) ions the copolymers selectively precipitated extracellularly expressed histidine-tagged single-chain Fv-antibody fragments (His6-scFv fragments) from the fermentation broth free from E. coli cells” (Abstract). Kumar further suggests step (c) isolating said antibody from said aggregate and (d) disassociating said aggregate, wherein said disassociating said aggregate comprises contacting said aggregate with a water soluble chelator under conditions that allow dissociation of said aggregate, wherein said water soluble chelator is EDTA and wherein said isolating said antibody comprises solubilizing said antibody (page 496 col. 2 para. 2). Note that Kumar teaches both step (c) and step (d) using EDTA to dissolve the aggregate, i.e. solubilize the antibody and disassociate the aggregate. Kumar further suggests (e) isolating said bathophenanthroline; and subsequently (f) contacting said bathophenanthroline, a non-ionic detergent and metal ions so as to generate a second aggregate comprising said bathophenanthroline, said detergent and said metal ions, thereby preparing the aggregate (page 495 col. 1 para. 2). Note that although Kumar fails to teach a bathophenanthroline, the reagent used by Kumar, i.e. the metal affinity macroligands, would inherently suggest to a person having ordinary skill in the art its application as the bathophenanthroline and subsequent isolation (step (e)) and contacting (step (f)) in the instant method of preparing an aggregate because it is a functional equivalent to the bathophenanthroline (the metal affinity macroligands also serve to form aggregates comprising metal ions for partitioning of an antibody (see Abstract of Kumar)).
Dutta teaches “[e]ngineered-membranes and engineered-micelles as efficient tools for purification of halorhodopsin and bacteriorhodopsin” (Title). Dutta teaches steps (a)-(c) but drawn to isolating a membrane protein (Abstract). Dutta further teaches that “[e]fficient pellet dissolution was observed in the presence of EDTA (50 mM) and imidazole (200 mM)” (page 205 col. 2 para. 4).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12454567 B2 to rely on the steps (d)-(f), wherein said disassociating said aggregate comprises contacting said aggregate with a water soluble chelator under conditions that allow dissociation of said aggregate, wherein said water soluble chelator comprises EDTA, and wherein said isolating said antibody comprises solubilizing said antibody taught by Kumar because Kumar suggests that this enables the reuse of the bathophenanthroline multiple times and U.S. Patent No. 12454567 B2 relies on bathophenanthroline. A person having ordinary skill in the art would have had a reasonable expectation of success because Dutta teaches that EDTA is capable of efficiently disassociating said aggregate comprising the bathophenanthroline. Furthermore, both U.S. Patent No. 12454567 B2, Kumar and Dutta teach methods related to preparing an aggregate.
Claim 8 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12454567 B2 in view of Kumar and Dutta as applied to claim 5 above, and further in view of Patchornik.
U.S. Patent No. 12454567 B2 in view of Kumar and Dutta fail to recite wherein said isolating said antibody from said aggregate comprises filtering said medium comprising said aggregate.
Patchornik further suggests wherein said isolating said antibody from said aggregate comprises filtering said medium comprising said aggregate (Figure 5B, page 29 lines 3-4 and 32-34). Patchornik suggests that this enables the removal/exclusion of impurities (page 20 lines 27-30).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12454567 B2 to rely on the filtering of said medium comprising said aggregate taught by Patchornik because Patchornik suggests that this enables the removal/exclusion of impurities. A person having ordinary skill in the art would have had a reasonable expectation of success because both Patchornik and U.S. Patent No. 12454567 B2 teach a method of isolating an antibody, the method comprising: (a) contacting bathophenanthroline, a non-ionic detergent and iron ions, so as to generate an aggregate comprising said bathophenanthroline, said detergent and said iron ions; and (b) contacting said aggregate with a medium comprising the antibody under conditions that allow partitioning of the antibody into said aggregate, thereby isolating the antibody.
Claim 25 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12454567 B2 in view of Patchornik.
Regarding claim 25, U.S. Patent No. 12454567 B2 recites steps (a)-(c) but drawn to an antibody, not a fragment thereof (claim 1).
U.S. Patent No. 12454567 B2 fails to recite antibody fragment.
Patchornik teaches a method of isolating an antibody fragment of interest (Title, Fig. 1, Abstract, page 9 lines 9-10) comprising: (a) contacting bathophenanthroline, a non-ionic detergent and iron ions so as to generate an aggregate comprising said bathophenanthroline, said detergent and said metal ions, wherein said non-ionic detergent is a polysorbate, a polyoxyethylene oleyl ether or octylphenol ethoxylate (Abstract, page 24 lines 15-19); (b) contacting said aggregate with a medium comprising: (i) an antibody fragment which comprises an Fc region and is devoid of an antigen binding region; and (ii) an antibody fragment which is devoid of an Fc region (page 11 lines 4 and 9-10) wherein said contacting is effected under conditions that allow selective partitioning of one of said fragments (i) or (ii) into said aggregate so as to generate an antibody fragment-enriched aggregate and an antibody fragment-enriched medium; and (c) isolating said antibody fragment of interest from said fragment-enriched aggregate or from said fragment-enriched medium, thereby isolating the antibody fragment of interest (Abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12454567 B2 to rely on the method being drawn to antibody fragments as taught by Patchornik because it would have been a simple matter of applying a known technique to a known method. In this case, both U.S. Patent No. 12454567 B2 and Patchornik teach the base method of isolating an antibody. Patchornik simply applies the art-recognized technique of using the method for isolating antibody fragments. Therefore, a person having ordinary skill in the art would have found it obvious to apply the technique taught by Patchornik to the meth taught by both references. A person having ordinary skill in the art would have had a reasonable expectation of success because both Patchornik and U.S. Patent No. 12454567 B2 teach a method of isolating an antibody, the method comprising: (a) contacting a bathophenanthroline, a non-ionic detergent and iron ions, so as to generate an aggregate comprising said bathophenanthroline, said detergent and said iron ions; and (b) contacting said aggregate with a medium comprising the antibody under conditions that allow partitioning of the antibody into said aggregate, thereby isolating the antibody.
Claims 26-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12454567 B2 in view of Patchornik as applied to claim 25 above, and further in view of Dutta.
Regarding claims 26-27, U.S. Patent No. 12454567 B2 in view of Patchornik recite the method of claim 25 as discussed above.
U.S. Patent No. 12454567 B2 in view of Patchornik fail to recite wherein said conditions comprise a pH of between 5-9, wherein said pH is between 7-8.
Kumar teaches “a detailed study of a new purification system using metal-loaded thermoresponsive copolymers as [metal affinity macroligands] AML. … When loaded with Cu(II) and Ni(II) ions the copolymers selectively precipitated extracellularly expressed histidine-tagged single-chain Fv-antibody fragments (His6-scFv fragments) from the fermentation broth free from E. coli cells” (Abstract). Kumar further teaches wherein said conditions comprise a pH of between 5-9, wherein said pH is between 7-8 (page 496 col. 2 para. 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 12454567 B2 in view of Patchornik to rely on the pH being between 7-8 taught by Kumar because Kumar suggests that this enables the isolation of antibodies from cell supernatant (using physiological pH) and U.S. Patent No. 12454567 B2 in view of Patchornik are concerned with methods of isolating antibodies. A person having ordinary skill in the art would have had a reasonable expectation of success because both U.S. Patent No. 12454567 B2 in view of Patchornik and Kumar teach methods drawn to isolating an antibody fragment using aggregates comprising a metal ions wherein the antibody partitions into the aggregate.
Response to Arguments
Applicant's arguments filed 4/14/2026 have been fully considered but they are not persuasive.
Regarding the previous 102 rejection of claim 4 (from Office Action 1/14/2026),
Applicant argues that “Patchornik does not disclose filtering a medium comprising aggregates for purposes of isolating the antibody. Rather, Patchornik dissolves the aggregate pellet and subsequently subjects the dissolved material to chromatographic polishing steps (see Patchornik, Fig. SB). These chromatographic steps occur after dissolution of the aggregates and therefore do not correspond to the claimed step of filtering the medium comprising the aggregate” (page 7 para. 1).
However, new grounds of rejection are set forth above in view of Wang (see rejection above). Wang suggests filtering a medium comprising aggregates for purposes of isolating the antibody and subsequently releasing the antibody from the aggregate (page 2 col. 2 para. 2 of Wang).
Regarding the 102 rejection of claim 25,
Applicant further argues that “Claim 25 has been amended to clarify the selective partitioning step recited therein. In particular, the claim now specifies that the antibody fragment comprising an Fc region partitions preferentially into the aggregate relative to the antibody fragment comprising an antigen binding region, thereby generating an antibody fragment-enriched aggregate and an antibody fragment-enriched medium. Support for this behavior is described in the specification (see e.g., page 32, lines 12-15). Amended claim 25 requires preferential partitioning of an Fc-containing fragment relative to an antigen-binding fragment. Patchornik contains no disclosure of selective partitioning between antibody fragments” (page 7 paras. 4-5).
However, contrary to Applicant’s remark, claim 25 fails to recite that the antibody fragment comprising an Fc region partitions preferentially into the aggregate relative to the antibody fragment comprising an antigen binding region. The claim merely recites “wherein said contacting is effected under conditions such that the antibody fragment which comprises an Fc region partitions preferentially into said aggregate relative to the antibody fragment which comprises an antigen binding region, so as to generate an antibody fragment-enriched aggregate and an antibody fragment-enriched medium” (emphasis added), that is a wherein clause that limits the contacting conditions of step (b). Applicant cites page 32 lines 12-15 of the specification as support: “An initial screen of the above and exemplary detergents representative of three different detergent types, illustrate preferential binding of the Fc domain (see for example Tween-60, BrijC10, Brij-S100 and Triton X-100 captured preferentially the Fc domain (Figure 9B)”. However, this part of the specification suggests that the partitioning of the Fc region is caused by the non-ionic detergent, which is taught by Patchornik (“Tween-20” page 24 lines 15-19), and fails to clarify the claimed “conditions”. The specification does suggest that the claimed contacting conditions are “having a level of salt below 100 mM” as per page 3 lines 28-29 of the specification and page 32 lines 20-25. Therefore, the claimed contacting conditions are interpreted as “having a level of salt below 100 mM” (see claim interpretation section above). Given that Patchornik teaches the required starting mixture of antibody fragments and the claimed contacting conditions, Patchornik anticipates the claim.
Regarding the 103 rejections,
Applicant argues that “Brown does not cure these deficiencies. Brown is a general review article concerning surfactants and magnetic liquids. While Brown may discuss combining non-ionic surfactants with iron salts, it does not disclose or suggest using such systems for partition-based isolation of antibodies into aggregates, filtering a medium comprising such aggregates to isolate antibodies, or modifying Patchornik' s process to adopt the claimed sequence of steps. The Examiner's rationale appears to rely on a general teaching that iron salts can be used with surfactants. However, this does not provide a sufficient reason to modify Patchornik in the specific manner required by the claims, particularly given that Patchornik already provides a complete purification workflow based on dissolution followed by chromatography…The cited art provides no reasonable expectation that such modification would succeed” (page 8 para. 3).
However, contrary to Applicant’s argument, a person having ordinary skill in the art would have found it obvious to modify Patchornik’s method to rely on the iron chloride taught by Brown because Brown suggests that this generates magnetic surfactants, which enable effective manipulation of biomolecules for protein separation and Patchornik is concerned with isolating antibodies, i.e. separating proteins. Also, contrary to Applicant’s argument, a person having ordinary skill in the art would have had a reasonable expectation of success because both Brown and Patchornik are drawn to methods of generating aggregates comprising non-ionic surfactant and iron salt for protein separation (see rejection above for the complete analysis).
Applicant further argues that “Kumar and Dutta do not cure these deficiencies… neither reference suggests applying a chelator-driven disassociation mechanism to Patchornik's aggregates, or recovering and reusing the chelator to reform aggregates, as required by the claims. The Examiner's rationale appears to rely on general similarities in metal-mediated systems. However, such generalizations do not provide a teaching, suggestion, or motivation to arrive at the specific multi-step regeneration process recited in the claims. The cited art provides no reasonable expectation that such modification would succeed” (page 8 last paragraph and page 9 para. 1).
However, Kumar does teach the chelator-driven disassociation mechanism claimed. Although, the dissociation taught by Kumar is not applied to the claimed aggregate, a person having ordinary skill in the art would have found it obvious to apply the chelator-driven disassociation mechanism taught by Kumar to Patchornik’s method because Kumar suggests this enables the reuse of the reagent used. A person having ordinary skill in the art would have had a reasonable expectation of success because Dutta teaches that the chelator-driven mechanism taught by Kumar is capable of efficiently disassociating an aggregate comprising the claimed bathophenanthroline. See rejection above for the complete analysis.
Applicant further argues that “Kumar's disclosure of pH conditions in unrelated purification systems does not suggest that such pH ranges would produce the specific selective partitioning behavior required by claim 25, nor be applicable to Patchornik's system in a manner that would achieve the claimed result. Similarly, Dutta does not disclose or suggest selective partitioning between antibody fragments based on structural differences. The Examiner's position appears to rely on the general optimization of pH. However, such optimization presupposes that the underlying selective partitioning mechanism is already known, which is not the case here. The cited art provides no reasonable expectation that such modification would succeed” (page 9 para. 3).
However, there is no deficiency in Patchornik regarding the selective partitioning being argued. Therefore, Applicant’s argument is not persuasive.
Regarding the double patenting rejections,
Applicant “requests deferring addressing issues of Double Patenting until indication of allowable subject matter” (page 11 para. 2).
However, no claim is allowed.
Conclusion
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/Fernando Ivich/Examiner, Art Unit 1678
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677
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