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 .
Claim Status
Applicants' response and amendments to the claims, filed 12/22/2025, are acknowledged and entered. No claims were cancelled or newly added.
Claims 1-12 and 18 are pending and under examination.
Information Disclosure Statement
Applicant’s Information Disclosure Statement filed 12/22/2025 has been received and entered into the present application. As reflected by the attached, completed copy of form PTO-1449, the Examiner has considered the cited references to the extent that they comply with the provisions of 37 C.F.R. §1.97, §1.98 and MPEP §609.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 1-8, 11-12 and 18 remain rejected under 35 U.S.C. 103(a) as being unpatentable over US PATENT NO. 10,376,499 (Issued August 13, 2019), RODVOLD ET AL. (Antimicrobial Agents and Chemotherapy, November 2018, vol. 62, no. 11, e01089-18, 11 pages), and SAGAN ET AL. (Antimicrobial Agents and Chemotherapy, March 2020, vol. 64, no. 3, e01506-19, 8 pages) in view of FDA, LYOPHILIZATION OF PARENTERAL (7/93) (U.S. Food & Drug Administration, Nov. 11, 2014, 21 pages), SNYDER (Lyophilization: The Basics, March 7, 2017, 8 pages), and UNASYN® DRUG LABEL (Pfizer, April 2018, 17 pages).
The claims are drawn to a lyophilized fixed dosage combination of durlobactam and sulbactam. Claim 1 is representative and reproduced below.
PNG
media_image1.png
112
630
media_image1.png
Greyscale
Regarding fixed dosage combinations of durlobactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof, US ‘499 teaches combinations of a b-lactamase inhibitor Compound 11 or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof.
PNG
media_image2.png
212
296
media_image2.png
Greyscale
(Abstract; col.3, l.26-59; Claims 1-4). Regarding claims 6-8, US ‘499 teaches Compound 1 and/or sulbactam may form stable pharmaceutically acceptable acid or base salts. Examples of base salts include alkali metal salts such as sodium, lithium, and potassium salts (col.9, l.62 to col.10, l.24). The sodium salt of Compound 1 is expressly exemplified and claimed (Claims 3 and 6). Regarding claims 11-12, US ‘499 teaches a method for treating a bacterial infection in a subject in need thereof consisting of administering to the subject an effective amount of compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of sulbactam, or a pharmaceutically acceptable salt thereof (Claim 5), wherein the bacterium is Acinetobacter spp. (Claim 9).
Regarding claims 1-5, 8, 11-12, and 18, RODVOLD ET AL. teach administering a fixed dosage combination of ETX25142 (1 g) and sulbactam (1 g) (ETX2514SUL) every 6 hours as a 3-hour i.v. infusion to healthy adult subjects (Abstract). They teach their data support further study of ETX2514SUL for the treatment of pneumonia caused by multidrug-resistant A. baumannii (Abstract).
Regarding claims 1-5, 8, 11, and 18, SAGAN ET AL. teach intravenously administering a combination of sulbactam (1 g) and durlobactam (1 g) (SUL-DUR 1:1 w/w) every 6 hours as a 3-hour i.v. infusion to adult subjects having complicated urinary tract infections (Abstract; p.6, “Materials and Methods”). They teach the treatments were “reconstituted and diluted in 100 ml of 0.9% saline”, which implies the treatments were stored in lyophilized form (p.6, “Materials and Methods”).
The combined teachings of US ‘499, Rodvold et al., and Sagan et al. thus clearly teach a combination of durlobactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof in a weight ratio of 1:1 for the treatment of bacterial infections, including multidrug-resistant A. baumannii infections. They differ from the instant claims only in so far as they do not expressly teach the durlobactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof are present as a ”co-lyophilized mixture”. However, as noted above Sagan et al. teach the sulbactam and durlobactam treatments were “reconstituted and diluted in 100 ml of 0.9% saline”, which implies the treatments were stored in lyophilized form.
FDA, LYOPHILIZATION OF PARENTERAL (7/93) teaches advantages of lyophilization include ease of processing a liquid, which simplifies aseptic handling, enhanced stability of a dry powder, removal of water without excessive heating of the product, enhanced product stability in a dry state, and rapid and easy dissolution of reconstituted product (p.1). It teaches there are many new parenteral products, including anti-infectives, which are manufactured as lyophilized products (p.2).
SNYDER teaches lyophilization is defined as a freeze-drying process that removes water from a product after it is frozen and placed under a vacuum. If the bulk drug ingredients are not stable in liquid or frozen form, lyophilization is necessary, which enables longer shelf life and makes it easier to transport the product (p.1). It teaches the same advantages of lyophilization taught by FDA cited above (p.2). It teaches 16 percent of the top 100 pharmaceutical drugs are lyophilized and 35 percent of biologic drugs are lyophilized. Additionally, it teaches more than 30 percent of the FDA-approved parenterals are lyophilized and soon more than half injectable drugs will require lyophilization (p.5).
UNASYN® DRUG LABEL teaches a fixed-dose combination of sulbactam sodium and ampicillin sodium present as a co-lyophilized mixture for reconstitution and intravenous administration to patients having a bacterial infection (Title; p.1-2, “Description”; p.13-14).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the present application to provide a co-lyophilized mixture of durlobactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof to be reconstituted in 0.9% saline for intravenous administration to a subject having a bacterial infection as expressly suggested and motivated by the combined teachings of the cited prior art. The formulation technique of lyophilization is well-established in the art and is routinely and commonly used for drugs administered parenterally (FDA, LYOPHILIZATION OF PARENTERAL (7/93) and SNYDER). Indeed, sulbactam sodium was already known in the art in a fixed dose combination with another antibacterial agent, ampicillin, present as a co-lyophilized mixture (UNASYN). The advantages of lyophilization were also well-known in the art, including simplifying aseptic handling, enhanced stability of a dry powder, removal of water without excessive heating of the product, enhanced product stability in a dry state, and rapid and easy dissolution of reconstituted product (FDA, LYOPHILIZATION OF PARENTERAL (7/93) and SNYDER). A combination of durlobactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof in a 1:1 weight ratio was also already known in the art and was already being administered intravenously to patients, including those having bacterial infections (Rodvold et al. and Sagan et al.).
One exemplary rationale for the Examiner’s determination of obvious is the application of a known technique (lyophilization) to a known product (fixed dosage combination of durlobactam and sulbactam) ready for improvement to yield predictable results. Here, the prior art teaches a “base” product (fixed dosage combination of durlobactam and sulbactam) upon which the claimed invention can be seen as an “improvement”, i.e., where the durlobactam and sulbactam are a co-lyophilized mixture. The prior art teaches the known formulation technique of lyophilization that is clearly applicable to the base fixed dosage combination of durlobactam and sulbactam taught in the prior art because the combination is administered is administered parenterally (intravenously). Indeed, Sagan et al. teach the durlobactam and sulbactam treatments were “reconstituted and diluted in 100 ml of 0.9% saline”, which implies the treatments were stored in lyophilized form, although they do not expressly teach they were present as a “co-lyophilized mixture”. Sulbactam sodium was in fact already known in the art in a fixed dose combination with another antibacterial agent, ampicillin, present as a co-lyophilized mixture (UNASYN). A person of ordinary skill in the art would have recognized that applying lyophilization to an antibacterial mixture of durlobactam and sulbactam intended for intravenous administration would have yielded predictable results, i.e., a co-lyophilized mixture of durlobactam and sulbactam suitable for reconstitution and intravenous administration to a patient. The skilled artisan would also have recognized the known benefits of such lyophilization, including simplifying aseptic handling, enhanced stability of a dry powder, removal of water without excessive heating of the product, enhanced product stability in a dry state, and rapid and easy dissolution of reconstituted product as expressly taught in the cited prior art.
Accordingly, the claimed invention is an application of a technique known in the prior art – the use of lyophilization to solve formulation problems of a pharmaceutical product. Those skilled in the art routinely use lyophilization for pharmaceutical products intended to be administered intravenously because such lyophilized formulations have many benefits and were known to solve numerous formulations problems, e.g., enhanced stability of a dry powder, enhanced product stability in a dry state, and rapid and easy dissolution of reconstituted product. The basic technique of lyophilization of a pharmaceutical product intended for intravenous administration would be expected to yield no more than the predictable outcome which one of ordinary skill would have expected to achieve with this common tool of the trade, i.e., a stable co-lyophilized mixture than is readily reconstituted for intravenous administration to a patient having a bacterial infection. Such is evidenced by UNASYN, which is a fixed dose combination of sulbactam sodium and a different antibacterial agent, ampicillin sodium, present as a co-lyophilized mixture for reconstitution and intravenous administration to patients having a bacterial infection.
Response to Arguments
While Applicant does not concede that a prima facie case of obviousness has been established, Applicant presents no arguments traversing the Examiner’s determination that the combined teachings of the cited prior art render the claimed invention prima facie obvious. Rather, Applicant argues that superiority and/or presence of an unexpected property can negate a prima facie showing under 35 U.S.C. 103. In this regard, Applicant argues:
PNG
media_image3.png
278
646
media_image3.png
Greyscale
Applicants appear to be relying the stability of the co-lyophilized mixture and the fact that it was able to be processed in a single vial, without clogging the equipment or leaving excessive residue. Applicant asserts that these results would not have been expected based on the Hausner ratio and compressibility index (CI) values of the co-lyophilized mixture.
Applicant’s unexpected results argument, i.e., that the “co-lyophilized mixture exhibited good stability at the long term storage conditions and was able to be processed in a single vial, without clogging the equipment or leaving excessive residue”, is unpersuasive for several reasons.
First, Applicant offers no evidence to support its attorney’s argument that the “good stability at the long term storage conditions” described in the Specification at Tables 2-4 would have been surprising to a skilled artisan in view of the teachings FDA, LYOPHILIZATION OF PARENTERAL (7/93) and SNYDER. See In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984) (“mere argument or conclusory statements in the specification” do not establish unexpected results). In this case both FDA and SNYDER teach that lyophilization provides enhanced stability of a dry powder. As Applicant did not compare the stability of the co-lyophilized mixture to anything, the “good stability at the long term storage conditions” observed by Applicant cannot be concluded to be surprising or unexpected.
Second, the improved flowability of the co-lyophilized mixture, i.e., that it was able to be processed in a single vial, without clogging the equipment or leaving excessive residue result appears to be unexpected based on the Hausner ratio and compressibility index (CI) values of the co-lyophilized mixture. However, the result Applicant points to in the Specification were for a specific co-lyophilized mixture comprising durlobactam sodium salt and sulbactam sodium salt in a 1:1 (w/w) ratio, whereas claim 1 encompasses “…durlolactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof…”, without limitation on pharmaceutically acceptable salt of durlobactam and/or sulbactam, the amounts thereof, or the w/w ratio thereof. Thus, Applicant has not shown that the result it cites is reasonably commensurate with the scope of the claims. See In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005) (explaining that evidence of unexpected results must be “commensurate in scope with the degree of protection sought by the claim[s]”).
For the above reasons and those already of record, claims 1-8, 11-12 and 18 remain properly rejected as being prima facie in view of the combined teachings of the cited prior art.
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. 9,968,593
Claims 1-8, 11-12 and 18 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 9,968,593 in view of RODVOLD ET AL. (Antimicrobial Agents and Chemotherapy, November 2018, vol. 62, no. 11, e01089-18, 11 pages), SAGAN ET AL. (Antimicrobial Agents and Chemotherapy, March 2020, vol. 64, no. 3, e01506-19, 8 pages), FDA, LYOPHILIZATION OF PARENTERAL (7/93) (U.S. Food & Drug Administration, Nov. 11, 2014, 21 pages), SNYDER (Lyophilization: The Basics, March 7, 2017, 8 pages), and UNASYN® DRUG LABEL (Pfizer, April 2018, 17 pages).
The ‘593 patent claims recite combinations comprising the b-lactamase inhibitor:
PNG
media_image4.png
104
144
media_image4.png
Greyscale
[durlobactam]
or a pharmaceutically acceptable salt thereof, sulbactam, or a pharmaceutically acceptable salt thereof, imipenem, or a pharmaceutically acceptable salt thereof, and cilastatin or a pharmaceutically acceptable salt thereof (Claim 1). The b-lactamase inhibitor is in the form of a sodium salt (Claim 2). The ‘593 patent also recite a method of treating bacterial infection in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of the β-lactamase inhibitor:
PNG
media_image4.png
104
144
media_image4.png
Greyscale
or a pharmaceutically acceptable salt thereof, an effective amount of sulbactam, or a pharmaceutically acceptable salt thereof, an effective amount of imipenem, or a pharmaceutically acceptable salt thereof, and an effective amount of cilastatin, or a pharmaceutically acceptable salt thereof (Claim 4), wherein the bacterial infection is caused by an Acinetobacter spp. pathogen, Pseudomonas aeruginosa, or a Burkholderia spp. pathogen (Claim 8).
The claims differ from the ‘593 patent claims in so far as they require the durlobactam and sulbactam are present as a co-lyophilized mixture.
Regarding claims 1-5, 8, 11-12, and 18, RODVOLD ET AL. teach administering a fixed dosage combination of ETX25143 (1 g) and sulbactam (1 g) (ETX2514SUL) every 6 hours as a 3-hour i.v. infusion to healthy adult subjects (Abstract). They teach their data support further study of ETX2514SUL for the treatment of pneumonia caused by multidrug-resistant A. baumannii (Abstract).
Regarding claims 1-5, 8, 11, and 18, SAGAN ET AL. teach intravenously administering a combination of sulbactam (1 g) and durlobactam (1 g) (SUL-DUR 1:1 w/w) every 6 hours as a 3-hour i.v. infusion to adult subjects having complicated urinary tract infections (Abstract; p.6, “Materials and Methods”). They teach the treatments were “reconstituted and diluted in 100 ml of 0.9% saline”, which implies the treatments were stored in lyophilized form (p.6, “Materials and Methods”).
FDA, LYOPHILIZATION OF PARENTERAL (7/93) teaches advantages of lyophilization include ease of processing a liquid, which simplifies aseptic handling, enhanced stability of a dry powder, removal of water without excessive heating of the product, enhanced product stability in a dry state, and rapid and easy dissolution of reconstituted product (p.1). It teaches there are many new parenteral products, including anti-infectives, which are manufactured as lyophilized products (p.2).
SNYDER teaches lyophilization is defined as a freeze-drying process that removes water from a product after it is frozen and placed under a vacuum. If the bulk drug ingredients are not stable in liquid or frozen form, lyophilization is necessary, which enables longer shelf life and makes it easier to transport the product (p.1). It teaches the same advantages of lyophilization taught by FDA cited above (p.2). It teaches 16 percent of the top 100 pharmaceutical drugs are lyophilized and 35 percent of biologic drugs are lyophilized. Additionally, it teaches more than 30 percent of the FDA-approved parenterals are lyophilized and soon more than half injectable drugs will require lyophilization (p.5).
UNASYN® DRUG LABEL teaches a fixed-dose combination of sulbactam sodium and ampicillin sodium present as a co-lyophilized mixture for reconstitution and intravenous administration to patients having a bacterial infection (Title; p.1-2, “Description”; p.13-14).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the present application to provide a co-lyophilized mixture of durlobactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof to be reconstituted in 0.9% saline for intravenous administration to a subject having a bacterial infection as expressly suggested and motivated by the combined teachings of the cited prior art. The formulation technique of lyophilization is well-established in the art and is routinely and commonly used for drugs administered parenterally (FDA, LYOPHILIZATION OF PARENTERAL (7/93) and SNYDER). Indeed, sulbactam sodium was already known in the art in a fixed dose combination with another antibacterial agent, ampicillin, present as a co-lyophilized mixture (UNASYN). The advantages of lyophilization were also well-known in the art, including simplifying aseptic handling, enhanced stability of a dry powder, removal of water without excessive heating of the product, enhanced product stability in a dry state, and rapid and easy dissolution of reconstituted product (FDA, LYOPHILIZATION OF PARENTERAL (7/93) and SNYDER). A combination of durlobactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof in a 1:1 weight ratio was also already known in the art and was already being administered intravenously to patients, including those having bacterial infections (Rodvold et al. and Sagan et al.).
One exemplary rationale for the Examiner’s determination of obvious is the application of a known technique (lyophilization) to a known product (fixed dosage combination of durlobactam and sulbactam) ready for improvement to yield predictable results. Here, the prior art teaches a “base” product (fixed dosage combination of durlobactam and sulbactam) upon which the claimed invention can be seen as an “improvement”, i.e., where the durlobactam and sulbactam are a co-lyophilized mixture. The prior art teaches the known formulation technique of lyophilization that is clearly applicable to the base fixed dosage combination of durlobactam and sulbactam taught in the prior art because the combination is administered is administered parenterally (intravenously). Indeed, Sagan et al. teach the durlobactam and sulbactam treatments were “reconstituted and diluted in 100 ml of 0.9% saline”, which implies the treatments were stored in lyophilized form, although they do not expressly teach they were present as a “co-lyophilized mixture”. Sulbactam sodium was in fact already known in the art in a fixed dose combination with another antibacterial agent, ampicillin, present as a co-lyophilized mixture (UNASYN). A person of ordinary skill in the art would have recognized that applying lyophilization to an antibacterial mixture of durlobactam and sulbactam intended for intravenous administration would have yielded predictable results, i.e., a co-lyophilized mixture of durlobactam and sulbactam suitable for reconstitution and intravenous administration to a patient. The skilled artisan would also have recognized the known benefits of such lyophilization, including simplifying aseptic handling, enhanced stability of a dry powder, removal of water without excessive heating of the product, enhanced product stability in a dry state, and rapid and easy dissolution of reconstituted product as expressly taught in the cited prior art.
Accordingly, the claimed invention is not patentably distinct from the ‘593 patent claims because it is an application of a technique known in the prior art – the use of lyophilization to solve formulation problems of a pharmaceutical product. Those skilled in the art routinely use lyophilization for pharmaceutical products intended to be administered intravenously because such lyophilized formulations have many benefits and were known to solve numerous formulations problems, e.g., enhanced stability of a dry powder, enhanced product stability in a dry state, and rapid and easy dissolution of reconstituted product. The basic technique of lyophilization of a pharmaceutical product intended for intravenous administration would be expected to yield no more than the predictable outcome which one of ordinary skill would have expected to achieve with this common tool of the trade, i.e., a stable co-lyophilized mixture than is readily reconstituted for intravenous administration to a patient having a bacterial infection. Such is evidenced by UNASYN, which is a fixed dose combination of sulbactam sodium and a different antibacterial agent, ampicillin sodium, present as a co-lyophilized mixture for reconstitution and intravenous administration to patients having a bacterial infection.
Accordingly, providing the dulbactam, sulbactam, imipenem, and cilstatin claimed in the ‘593 patent as a co-lyophilized mixture for reconstitution and intravenous administration to a subject having a bacterial infection would have been prima facie obvious to a person of ordinary skill in the art.
U.S. Patent No. 10,376,499
Claims 1-8, 11-12 and 18 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 10,376,499 in view of RODVOLD ET AL. (Antimicrobial Agents and Chemotherapy, November 2018, vol. 62, no. 11, e01089-18, 11 pages), SAGAN ET AL. (Antimicrobial Agents and Chemotherapy, March 2020, vol. 64, no. 3, e01506-19, 8 pages), FDA, LYOPHILIZATION OF PARENTERAL (7/93) (U.S. Food & Drug Administration, Nov. 11, 2014, 21 pages), SNYDER (Lyophilization: The Basics, March 7, 2017, 8 pages), and UNASYN® DRUG LABEL (Pfizer, April 2018, 17 pages).
The ‘499 patent claims recite combinations consisting essentially of the b-lactamase inhibitor:
PNG
media_image4.png
104
144
media_image4.png
Greyscale
[durlobactam]
or a pharmaceutically acceptable salt thereof, and sulbactam, or a pharmaceutically acceptable salt thereof (Claim 1), and optionally further comprising ampicillin or cefoperazone (Claims 2 and 4). The b-lactamase inhibitor is in the form of a sodium salt (Claim 3). The ‘499 patent also recites a method of treating bacterial infection in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of the β-lactamase inhibitor:
PNG
media_image4.png
104
144
media_image4.png
Greyscale
or a pharmaceutically acceptable salt thereof, and an effective amount of sulbactam, or a pharmaceutically acceptable salt thereof (Claim 5), wherein the bacterial infection is caused by an Acinetobacter spp. pathogen, Pseudomonas aeruginosa, or a Burkholderia spp. pathogen (Claim 9).
The claims differ from the ‘499 patent claims in so far as they require the durlobactam and sulbactam are present as a co-lyophilized mixture.
Regarding claims 1-5, 8, 11-12, and 18, RODVOLD ET AL. teach administering a fixed dosage combination of ETX25144 (1 g) and sulbactam (1 g) (ETX2514SUL) every 6 hours as a 3-hour i.v. infusion to healthy adult subjects (Abstract). They teach their data support further study of ETX2514SUL for the treatment of pneumonia caused by multidrug-resistant A. baumannii (Abstract).
Regarding claims 1-5, 8, 11, and 18, SAGAN ET AL. teach intravenously administering a combination of sulbactam (1 g) and durlobactam (1 g) (SUL-DUR 1:1 w/w) every 6 hours as a 3-hour i.v. infusion to adult subjects having complicated urinary tract infections (Abstract; p.6, “Materials and Methods”). They teach the treatments were “reconstituted and diluted in 100 ml of 0.9% saline”, which implies the treatments were stored in lyophilized form (p.6, “Materials and Methods”).
FDA, LYOPHILIZATION OF PARENTERAL (7/93) teaches advantages of lyophilization include ease of processing a liquid, which simplifies aseptic handling, enhanced stability of a dry powder, removal of water without excessive heating of the product, enhanced product stability in a dry state, and rapid and easy dissolution of reconstituted product (p.1). It teaches there are many new parenteral products, including anti-infectives, which are manufactured as lyophilized products (p.2).
SNYDER teaches lyophilization is defined as a freeze-drying process that removes water from a product after it is frozen and placed under a vacuum. If the bulk drug ingredients are not stable in liquid or frozen form, lyophilization is necessary, which enables longer shelf life and makes it easier to transport the product (p.1). It teaches the same advantages of lyophilization taught by FDA cited above (p.2). It teaches 16 percent of the top 100 pharmaceutical drugs are lyophilized and 35 percent of biologic drugs are lyophilized. Additionally, it teaches more than 30 percent of the FDA-approved parenterals are lyophilized and soon more than half injectable drugs will require lyophilization (p.5).
UNASYN® DRUG LABEL teaches a fixed-dose combination of sulbactam sodium and ampicillin sodium present as a co-lyophilized mixture for reconstitution and intravenous administration to patients having a bacterial infection (Title; p.1-2, “Description”; p.13-14).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the present application to provide a co-lyophilized mixture of durlobactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof to be reconstituted in 0.9% saline for intravenous administration to a subject having a bacterial infection as expressly suggested and motivated by the combined teachings of the cited prior art. The formulation technique of lyophilization is well-established in the art and is routinely and commonly used for drugs administered parenterally (FDA, LYOPHILIZATION OF PARENTERAL (7/93) and SNYDER). Indeed, sulbactam sodium was already known in the art in a fixed dose combination with another antibacterial agent, ampicillin, present as a co-lyophilized mixture (UNASYN). The advantages of lyophilization were also well-known in the art, including simplifying aseptic handling, enhanced stability of a dry powder, removal of water without excessive heating of the product, enhanced product stability in a dry state, and rapid and easy dissolution of reconstituted product (FDA, LYOPHILIZATION OF PARENTERAL (7/93) and SNYDER). A combination of durlobactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof in a 1:1 weight ratio was also already known in the art and was already being administered intravenously to patients, including those having bacterial infections (Rodvold et al. and Sagan et al.).
One exemplary rationale for the Examiner’s determination of obvious is the application of a known technique (lyophilization) to a known product (fixed dosage combination of durlobactam and sulbactam) ready for improvement to yield predictable results. Here, the prior art teaches a “base” product (fixed dosage combination of durlobactam and sulbactam) upon which the claimed invention can be seen as an “improvement”, i.e., where the durlobactam and sulbactam are a co-lyophilized mixture. The prior art teaches the known formulation technique of lyophilization that is clearly applicable to the base fixed dosage combination of durlobactam and sulbactam taught in the prior art because the combination is administered is administered parenterally (intravenously). Indeed, Sagan et al. teach the durlobactam and sulbactam treatments were “reconstituted and diluted in 100 ml of 0.9% saline”, which implies the treatments were stored in lyophilized form, although they do not expressly teach they were present as a “co-lyophilized mixture”. Sulbactam sodium was in fact already known in the art in a fixed dose combination with another antibacterial agent, ampicillin, present as a co-lyophilized mixture (UNASYN). A person of ordinary skill in the art would have recognized that applying lyophilization to an antibacterial mixture of durlobactam and sulbactam intended for intravenous administration would have yielded predictable results, i.e., a co-lyophilized mixture of durlobactam and sulbactam suitable for reconstitution and intravenous administration to a patient. The skilled artisan would also have recognized the known benefits of such lyophilization, including simplifying aseptic handling, enhanced stability of a dry powder, removal of water without excessive heating of the product, enhanced product stability in a dry state, and rapid and easy dissolution of reconstituted product as expressly taught in the cited prior art.
Accordingly, the claimed invention is not patentably distinct from the ‘499 patent claims because it is an application of a technique known in the prior art – the use of lyophilization to solve formulation problems of a pharmaceutical product. Those skilled in the art routinely use lyophilization for pharmaceutical products intended to be administered intravenously because such lyophilized formulations have many benefits and were known to solve numerous formulations problems, e.g., enhanced stability of a dry powder, enhanced product stability in a dry state, and rapid and easy dissolution of reconstituted product. The basic technique of lyophilization of a pharmaceutical product intended for intravenous administration would be expected to yield no more than the predictable outcome which one of ordinary skill would have expected to achieve with this common tool of the trade, i.e., a stable co-lyophilized mixture than is readily reconstituted for intravenous administration to a patient having a bacterial infection. Such is evidenced by UNASYN, which is a fixed dose combination of sulbactam sodium and a different antibacterial agent, ampicillin sodium, present as a co-lyophilized mixture for reconstitution and intravenous administration to patients having a bacterial infection.
Accordingly, providing the dulbactam, sulbactam, and optionally also the ampicillin, claimed in the ‘499 patent as a co-lyophilized mixture for reconstitution and intravenous administration to a subject having a bacterial infection would have been prima facie obvious to a person of ordinary skill in the art.
Response to Arguments
Applicant proffers no specific arguments traversing these rejections. Rather Applicant argues:
PNG
media_image5.png
116
616
media_image5.png
Greyscale
The Examiner’s response to Applicant’s arguments pertaining to the 35 U.S.C. 103 rejection above are herein incorporated by reference in their entirety. For the same reasons Applicant’s arguments were not persuasive to overcome the 35 U.S.C. 103 rejection, they are likewise not persuasive to overcome the nonstatutory double patenting rejections.
Allowable Subject Matter
Claims 9-10 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Claims 1-8, 11-12, and 18 are rejected.
Claims 9-10 are objected to.
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Applicant is requested to specifically point out the support for any amendments made to the disclosure in response to this Office action, including the claims (M.P.E.P. §§ 714.02 and 2163.06). In doing so, applicant is requested to refer to pages and line (or paragraph) numbers (if available) in the as-filed specification, not the published application. Due to the procedure outlined in M.P.E.P. § 2163.06 for interpreting claims, other art may be applicable under 35 U.S.C. § 102 or 35 U.S.C. § 103(a) once the aforementioned issue(s) is/are addressed.
Applicant is reminded that MPEP §2001.06(b) clearly states that “[t]he individuals covered by 37 C.F.R. 1.56 have a duty to bring to the attention of the examiner, or other Office official involved with the examination of a particular application, information within their knowledge as to other copending United States applications which are "material to patentability" of the application in question." See Armour & Co. v. Swift & Co., 466 F.2d 767, 779, 175 USPQ 70, 79 (7th Cir. 1972). MPEP §2001.06(b) clearly indicates that “if a particular inventor has different applications pending in which similar subject matter but patentably indistinct claims are present that fact must be disclosed to the examiner of each of the involved applications.” See Dayco Prod. Inc. v. Total Containment, Inc., 329 F.3d 1358, 1365-69, 66 USPQ2d 1801, 1806-08 (Fed. Cir. 2003).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES D ANDERSON whose telephone number is (571)272-9038. The examiner can normally be reached on Monday-Friday, 7:30 am - 4:00 pm PST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Lundgren can be reached on 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/James D. Anderson/Primary Examiner, Art Unit 1629
UNITED STATES PATENT AND TRADEMARK OFFICE
500 Dulany Street
Alexandria, VA 22314-5774
Tel. No.: (571) 272-9038
1 Compound 1 as taught in WO ‘452 is durlobactam as evidenced by Applicants’ disclosure at [0017].
2 ETX2514 as taught in Rodvold et al. is durlobactam as evidenced by Applicants’ disclosure at [0017].
3 ETX2514 as taught in Rodvold et al. is durlobactam as evidenced by Applicants’ disclosure at [0017].
4 ETX2514 as taught in Rodvold et al. is durlobactam as evidenced by Applicants’ disclosure at [0017].