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 .
DETAILED ACTION
Response to Amendment
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office Action has been withdrawn pursuant to 37 CFR 1.114.
The Information Disclosure Statements (IDS) filed 13 July 2026 and 11 August 2026 have been entered. Applicant’s amendment of the claims filed 2 June 2026 has been entered. Applicant’s remarks filed 2 June 2026 are acknowledged.
Claims 6, 13, 15, 20-31 and 33-48 are cancelled. Claims 1-5, 7-12, 14, 16-19, 32 and 49-53 are pending. Claim 32 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Claims 1-5, 7-12, 14, 16-19 and 49-53 are under examination to the extent they read on the elected species: A-a) wherein the surfactant is a polysorbate; and B) wherein the bispecific antibody construct comprises a polypeptide having the amino acid sequence of SEQ ID NO: 78.
Claim Objections/Rejections Withdrawn
The objections to claims 1 and 7 for informalities are withdrawn in response to Applicant’s amendment of the claims.
The objection to claims 52 and 53 for using acronyms without first defining what they represent (e.g., “PVC”, “EVA”) is withdrawn in response to Applicant’s amendment of the claims.
The rejection of claim 5 under 35 U.S.C. 112(b), as being indefinite for lacking antecedent basis for the limitation “the surfactant”, is withdrawn in response to Applicant’s amendment of the claim.
Claim Rejections Maintained
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 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-5, 7-10, 12, 14, 16-19 and 49-53 remain rejected under 35 U.S.C. 103, as being unpatentable over Olbrich et al. (US 2015/0335706 A1, Pub. Date: Nov. 26, 2015), in view of Zhu (CN 103387723 A, Pub. Date: November 13, 2013).
Ground of Rejection
Olbrich teaches a liquid pharmaceutical composition comprising a polypeptide, i.e., Bispecific T-cell Engager or BiTE®, wherein the polypeptide comprises two scFv antigen-binding domains, the first scFv binding domain binds to human CD3 epsilon, and the second scFv binding domain binds to a cell surface antigen [0040] [0042] [0204] [0205]. Olbrich teaches that the first binding domain comprises the amino acid sequence of SEQ ID NO: 5 [0046] [0209], which is identical to SEQ ID NO: 201 of the instant application (sequence alignment provided previously). Olbrich teaches an exemplary BiTE®, e.g., PSMA-BiTE1, with the amino acid sequence of SEQ ID NO: 8, which comprises SEQ ID NO: 167 of the instant application (sequence alignment provided previously). Olbrich teaches that the liquid pharmaceutical composition comprising the polypeptide in a concentration of from 0.5 mg/ml to 0.2 mg/ml [0223]. Olbrich teaches that the composition contains 0.04% polysorbate 80 [0239]. The CMC of polysorbate 80 is in the range of 0.001% to 0.006% w/v. Therefore, Olbrich meets the limitation of the polysorbate concentration as required in claims 1 and 7. Regarding claim 49, Olbrich teaches that useful polysorbates (as a wetting agent) include polysorbate 20 or 80 in a concentration from 0.002% to 0.1%, preferably from 0.04% to 0.1% [0089] [0090]. Olbrich teaches that the composition contains Tris and phosphate (e.g., sodium phosphate), and the composition has a pH in a range of about 5.0-7.0 [0039] [0228-0233]. Olbrich teaches that the composition additionally contains trehalose dihydrate, e.g., about 4% [0243]. Olbrich teaches that a BiTE® formulation, which comprises 50 mM phosphate, 100 mM Tris, 0.04% polysorbate 80, and 4% trehalose dihydrate, at a pH of 6.0, is capable of stabilizing PSMA-BiTE1 with respect to the formation of aggregates, and this applies both to low concentrations in the range of below mg/ml and to high concentrations of >2 mg/ml [0010]. Olbrich further shows that a PSMA-BiTE1 aqueous solution diluted with 0.9% NaCl solution and containing 0.004% polysorbate and PSMA-BiTE1 at a concentration of 2 mg/ml was stable over a storage period of 9 days (see Example 21). Olbrich teaches that the composition is suitable for as intravenous injection or infusion [0134].
Olbrich teaches as set forth above. Olbrich, however, does not teach wherein the liquid pharmaceutical composition is contained inside a container, which is made of a plastic substantially free di-2-ethylhexyl phthalate (DEHP) or tri-2- ethylhexyltrimellitate (TOTM) (claim 1), and wherein the plastic container that is substantially free of DEHP or TOTM is made of a material comprising PVC (claims 52-53).
Zhu teaches that dihexyl phthalate (DEHP)-plasticized polyvinyl chloride (PVC) has been used as the main raw material to produce disposable infusion sets, however, the safety of DEHP has attracted attention especially in the food and medical fields [0004] [0005]. Zhu teaches several detrimental effects that DEHP can cause in human, including cancer [0006-0009]. Zhu teaches that currently used infusion set components, such as drip bottles and tubing, are made of DEHP-plasticized PVC, which contains a large amount of DEHP; during infusion, DEHP easily dissolves in the medication and enters the bloodstream along with the medication, increasing safety risks and causing infusion-related harm to the human body [0011]. Zhu discloses a DEHP-free PVC material and infusion set made therefrom that are inert at room temperature, reducing the leaching of harmful substances, and allowing for safe and reliable use in the medical and health fields [0013] [0017].
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 use the infusion set made from a DEHP-free PVC material for administering the liquid pharmaceutical composition of Olbrich. One of ordinary skill in the art would have been motivated to do so, because Olbrich teaches a liquid pharmaceutical composition comprising a BiTE® molecule that is suitable for intravenous infusion, and Zhu teaches an infusion set made from a DEHP-free PVC material which can avoid the infusion-related harm from DEHP leached from an infusion set. Therefore, the combined teachings provide a reasonable expectation of success in treating the patient.
Response to Applicant’s Arguments
Applicant argues that the claimed invention demonstrates important improvements to the storage and dosing accuracy of antibody constructs in aqueous solution and stored in containers made of particular material. Applicant argues that the instant specification discloses the surprising findings that surfactants, when used at a concentration of at least 0.25x of their critical micelle concentration (CMC), can stabilize proteins at low concentrations in liquid compositions and effectively prevent protein loss due to adsorption to solid surfaces; further, the presence polysorbates (but not poloxamers) in formulation contributes to leaching of DEHP or TOTM from the container material (PVC-DEHP IV bags) into the composition contained therein. Applicant argues that instant application provides a composition/container combination that not only minimizes protein loss but also addresses the issue of leaching of container material into pharmaceutical compositions by identifying (and avoiding) previously unknown conditions which result in leaching.
Applicant further argues that the Office has not identified a reason to combine a polysorbate-containing BiTE® antibody construct formulation specifically with a DEHP-free container; and the cited art does not teach or suggest that polysorbate-containing compositions have a particular need for DEHP-free containers. Applicant argues that with regard to the surfactant, Olbrich provides no specific teaching or suggestion that would motivate the skilled artisan to select a polysorbate out of the myriad options; with regard to a container, Olbrich does not delineate between DEHP-containing and DEHP-free container materials, thus requiring that the skilled artisan select both plastic over any other material type and select a DEHP-free material over a DEHP-containing material to arrive at the instant claims; and with regard to the bispecific antibody concentrations and surfactant concentrations, Olbrich discloses the bispecific antibody concentrations and surfactant concentrations beyond those claimed herein. Applicant also argues that intravenous infusion is not the exclusive administration modality contemplated by Olbrich, as the reference states that the liquid compositions are suitable for other routes of administration, such as subcutaneous injection, and the Office cited no reasoning as to why one of ordinary skill would select intravenous administration over the others disclosed by the reference.
Applicant argues that Zhu does not remedy the defects of Olbrich because it does not identify any mechanism by which a liquid composition causes DEHP to leach from PVC; further, Zhu does not identify which specific component(s) of a liquid composition contribute to leaching of DEHP from DEHP-containing PVC. Applicant further cited several references and argues that the state of the art as of the effective filing date does not evidence a trend to avoid DEHP in medical equipment, and the FDA sound minimal risk posed by exposure to the amount of DEHP released from PVC bags used to store and administer drugs.
Applicant’s arguments have been fully considered but have not been found to be persuasive.
Olbrich teaches a liquid pharmaceutical composition comprising a Bispecific T-cell Engager or BiTE® (a bispecific antibody construct), wherein the antibody construct is present in a concentration of from 0.5 mg/ml to 0.2 mg/ml [0223]. Olbrich teaches that the composition contains 0.04% polysorbate 80 [0239]. The CMC of polysorbate 80 is in the range of 0.001% to 0.006% w/v, thus, the polysorbate concentration in the liquid pharmaceutical composition of Olbrich is at least about 0.25x (or between about 0.25x and about 20x) of the CMC, as required by the present claims. Olbrich teaches an exemplary BiTE® formulation, which comprises 50 mM phosphate, 100 mM Tris, 0.04% polysorbate 80, and 4% trehalose dihydrate, at a pH of 6.0; and Olbrich teaches that this formulation is capable of stabilizing PSMA-BiTE1 both at low concentrations in the range of below mg/ml and at high concentrations of >2 mg/ml [0010]. Olbrich further shows that a PSMA-BiTE1 aqueous solution diluted with 0.9% NaCl solution and containing 0.004% polysorbate and PSMA-BiTE1 at a concentration of 2 mg/ml was stable over a storage period of 9 days (see Example 21). Thus, contrary to Applicant’s arguments that Olbrich only contemplates use of any surfactant with no preference given to any particular surfactant, Olbrich specifically teaches an exemplary formulation that contains a BiTE® molecule (PSMA-BiTE1) and a polysorbate with both components at the same concentrations as recited in the instant claims. Olbrich provides specific teaching such that a person skilled in the art would readily select a polysorbate and its concentration for formulating an antibody construct with a concentration as recited in the instant claims. Regarding Applicant’s unexpected findings that the use of a polysorbate can stabilize proteins at low concentrations in liquid compositions and effectively prevent protein loss due to absorption to solid surfaces, such effects are also taught by Olbrich. Olbrich teaches that to prevent the adsorption of the PSMA-BiTE1 molecules on the vessel wall of injection syringes, infusion bags, etc., it is sufficient to have just 0.002% polysorbate 80 [0010].
Regarding the container material, Olbrich teaches that the containers can, for example, be composed of glass or plastic [0118]. Olbrich teaches that the composition is suitable for as intravenous injection or infusion and can be contained in infusion bags [0010] [0134]. While Olbrich does not teach wherein the container is made of a plastic substantially free di-2-ethylhexyl phthalate (DEHP) or tri-2- ethylhexyltrimellitate (TOTM) (claim 1), and wherein the plastic container that is substantially free of DEHP or TOTM is made of a material comprising PVC (claims 52-53), Zhu renders this feature obvious. Zhu teaches that currently used infusion set components, such as drip bottles and tubing, are made of DEHP-plasticized PVC, which contains a large amount of DEHP; during infusion, DEHP easily dissolves in the medication and enters the bloodstream along with the medication, increasing safety risks and causing infusion-related harm to the human body [0011]. Zhu discloses a DEHP-free PVC material and infusion set made therefrom that are inert at room temperature, reducing the leaching of harmful substances, and allowing for safe and reliable use in the medical and health fields [0013] [0017]. 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 use the infusion set made from a DEHP-free PVC material for administering the liquid pharmaceutical composition of Olbrich. One of ordinary skill in the art would have been motivated to do so and have a reasonable expectation of success, because Olbrich teaches a liquid pharmaceutical composition comprising a BiTE® molecule that is suitable for intravenous infusion, and Zhu teaches an infusion set made from a DEHP-free PVC material which can avoid the infusion-related harm from DEHP leached from an infusion set and allow for safe and reliable use in the medical and health fields.
With respect to Applicant’s arguments that intravenous infusion is not the exclusive administration modality contemplated by Olbrich and the Office cited no reasoning as to why one of ordinary skill would select intravenous administration over the other routes disclosed by the reference, the Examiner acknowledges that the liquid pharmaceutical composition of Olbrich can be administered by other routes, such as subcutaneous injection, intramuscular injection, intraperitoneal injection, etc. However, when the composition is administered by intravenous injection or infusion, one skilled in the art would be motivated to use an infusion set made from a DEHP-free PVC material as taught by Zhu, such that it can avoid the infusion-related harm from DEHP leached from an infusion set.
Regarding the unexpected results shown in the specification, specifically, the findings that polysorbates, but not poloxamers, caused significant leaching of DEHP from PVC-DEHP IV bags, the Examiner acknowledges that Zhu does not teach the mechanism or identify which specific component(s) of a liquid composition contribute to leaching of DEHP from DEHP-containing PVC. However, Zhu recognized the safety issue of DEHP leached from infusion set components (e.g., drip bottles and tubing) made from DEHP-plasticized PVC. Zhu discloses a DEHP-free PVC material and infusion sets made therefrom that are inert at room temperature, reducing the leaching of harmful substances, and allowing for safe and reliable use in the medical and health fields. Thus, Zhu provides an alternative that would solve the problem of DEHP leaching from an infusion set, no matter what component(s) in the drug formulation (e.g., whether it is a polysorbate or another identified/unidentified molecule) cause the DEHP leaching. One of ordinary skill in the art would have been motivated to use Zhu’s infusion set because it can avoid the infusion-related harm from DEHP leached from an infusion set. By doing so, it would arrive at the same composition/container combination as claimed in the present application.
With respect to Applicant’s arguments that as of the effective filing date, the state of the art does not evidence a trend to avoid DEHP in medical equipment, however, the numerous documents cited by Applicant evidence that there was a safety concern related to administration of drugs using infusion bags that can leach DEHP into the drug solution. For example, the FDA document provided by Applicant (“Safety Assessment of Di(2-ethylhexyl)phthalate (DEHP) Released from PVC Medical Devices”) describes the safety concern of leached DEHP from medical devices in humans, and instructs the user to administer and store the reconstituted drug in PVC bags that release minimal amounts of DEHP for intravenous administration.
“The potential for (DEHP) and other phthalate esters to produce adverse effects in humans has been the subject of considerable discussion and debate in the scientific community, as well as attention by the media. Although the toxic and carcinogenic effects of DEHP have been well established in experimental animals, the ability of this compound to produce these effects in humans is controversial.” (p. 8, 2nd paragraph)
“The various panels described above have been convened largely to address a series of controversial issues regarding the potential health risk posed by human exposure to DEHP. Following a review of the available data, these groups have reached differing opinions regarding the health risk posed by exposure to DEHP. For example, expert panel chaired by Dr. Koop for the ACSH concluded that there is little or no harm posed by patient exposure to DEHP. … In contrast, the expert panel convened by the CERHR felt that exposure of critically ill neonates to DEHP represented a “serious concern” and HCWH has concluded that the potential risks of associated with patient exposure to DEHP are significant enough to require regulatory initiatives including labeling of PVC devices and to move toward alternatives to PVC. Over the years, a number of individual investigators have also suggested that DEHP exposure may pose a risk to patients, whereas others have suggested that there is little or no risk, particularly with regard to the carcinogenic effects of DEHP.” (p. 8, 4th paragraph)
“The package insert labeling that accompanies a number of drug products, notably antineoplastics (e.g., paclitaxel, docetaxel, tacrolimus, teniposide), cautions against the use of PVC containers and administration sets for delivery of the drug. If non-PVC containers and non-PVC infusion sets are used to administer the drug, DEHP exposure is expected to be minimal.” (p. 12, 4th paragraph)
“The labeling information provided with a number of other drugs (ciprofloxacin, cefoperazone sodium, fluconazole, metronidazole HCl, cimetidine) instructs the user to administer and store the reconstituted drug in PVC bags that release minimal amounts of DEHP, such as Baxter’s PL-146 bag. The concentration of DEHP in these bags is assumed to not exceed 5 ppm (5 g/ml).” (p. 12, 5th paragraph)
Clearly, as of the effective filing date, the state of the art would encourage the use of non-PVC infusion sets or PVC bags that release minimal amounts of DEHP for intravenous administration of drugs. Zhu teaches infusion sets made from a DEHP-free PVC material that are inert at room temperature, reducing the leaching of harmful substances, and allowing for safe and reliable use in the medical and health fields. Thus, combining the liquid pharmaceutical composition of Olbrich with the infusion set of Zhu provides a reasonable expectation of success in administering the antibody drug via intravenous infusion without a risk of DEHP exposure in the patient.
For the foregoing reasons, the combined teachings of Olbrich and Zhu render the instant claims obvious.
Claims 11 and 19 remain rejected under 35 U.S.C. 103, as being unpatentable over Olbrich et al. (US 2015/0335706 A1), in view of Zhu (CN 103387723 A), and further in view of Raum et al. (US 2017/0218078 A1, Pub. Date: Aug. 3, 2017).
Applicant argues that for at least the reasons set forth above, the combination of Olbrich and Zhu fails to render the pharmaceutical preparation of claim 1 obvious, and Raum does not remedy the defects of Olbrich and Zhu.
Applicant’s arguments have been fully considered but have not been found to be persuasive.
Applicant’s arguments regarding the teachings of Olbrich and Zhu have been addressed above. Raum is further cited to remedy the defects in Olbrich and Zhu, which do not teach wherein the bispecific construct further comprises a third domain comprising, in an amino to carboxyl order, hinge-CH2 domain-CH3 domain-linker-hinge-CH2 domain-CH3 domain (claim 11), and wherein the bispecific antibody construct comprises a polypeptide having the amino acid sequence of SEQ ID NO: 78 (the elected species) (claim 19).
Raum teaches that the fusion of a specific Fc modality, i.e. the third domain, to a BiTE molecule comprising two scFv antigen-binding domains significantly prolonged half-life of the bispecific antibody construct ([0014-0018] [0087]). Raum teaches that the third domain comprises in an N- to C-terminal order, hinge-CH2 domain-CH3 domain-linker-hinge-CH2 domain-CH3 domain [0079]. Raum teaches a bispecific DLL3xCD3 antibody construct set forth in SEQ ID NO: 520, which is identical to SEQ ID NO: 78 of the instant application (sequence alignment provided previously).
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 make a fusion between the BiTE® molecule disclosed in Olbrich and the third domain taught by Raum. One of ordinary skill in the art would have been motivated to do so, because Olbrich and Zhu teach a liquid pharmaceutical composition comprising a BiTE® molecule comprising two scFv antigen-binding domains, and Raum teaches that the fusion of the third domain to a BiTE® molecule can significantly prolong half-life of the bispecific antibody construct. Therefore, the combined teachings provide a reasonable expectation of success in making a liquid pharmaceutical composition comprising a BiTE® molecule that has a prolonged half-life.
Double Patenting
Claims 1, 4-5, 7-10, 12, 14 and 16-18 and 50-53 remain rejected on the ground of nonstatutory double patenting as being unpatentable over:
1) claims 1, 5-12 and 18-19 of U.S. Patent No. 11,419,933; and
2) claims 1-5, 7, 9-10 and 15-17 of U.S. Patent No. 12,617,853 (previously over Application No. 16/482,603).
Applicant argues that at least for the reasons set forth in the response to the 103 rejection, neither the claims of the ‘993 and ‘853 patents signal leaching as a problem in the art, nor the claims reference container material comprising or substantially free of DEHP or TOTM, and the skilled artisan would not be motivated to look to Zhu in view of the ‘993 or ‘853 patent claims.
Applicant’s arguments have been fully considered but have not been found to be persuasive.
Applicant’s arguments regarding the DEHP leaching problem and the use of a container material comprising or substantially free of DEHP or TOTM have been addressed above. The claims of the ‘933 patent and the ‘853 patent recite a liquid pharmaceutical composition comprising a bispecific single chain antibody construct of the subject claims, wherein the bispecific single chain antibody construct is present in a concentration range of 0.1-5 mg/ml or 0.1-8 mg/ml, and wherein the pharmaceutical composition comprises polysorbate 80 at a concentration of about 0.01% (w/v). Regarding the plastic container for the liquid pharmaceutical composition, Zhu (CN 103387723 A, cited above) teaches and renders obvious of using a plastic container made from a DEHP-free PVC material such that it can avoid the infusion-related harm from PVC-leached DEHP (see above 103 section). Therefore, the instant claims are obvious over the claims of the ‘933 patent and the ‘853 patent in view of Zhu.
Conclusion
NO CLAIM IS ALLOWED.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Xiaozhen Xie, whose telephone number is 571-272-5569. The examiner can normally be reached on M-F, 8:30-5.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa L. Ford, can be reached on 571-272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/XIAOZHEN XIE/Primary Examiner, Art Unit 1674
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