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 .
Continued Examination Under 37 CFR 1.114
1. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11 March 2026 has been entered.
Status of the Application
2. The amendments and response filed 10 June 2024 is acknowledged and has been considered in its entirety. Claims 1, 6-12, 15-17, and 19-22 are pending and subject to examination on the merits. Claims 15 and 20-22 are withdrawn from consideration as being drawn to non-elected subject matter. Claims 1, 6-12, 16-17, and 19 are currently under examination.
Priority
3. Acknowledgement is made of applicant’s claim for foreign priority based on an application filed in EP (EP19188904.7) on 29 July 2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Withdrawn Rejections
4. The rejection of claims 1, 6-9, 11-12, and 16-17 as obvious over the teachings of Grallert et al (Grallert et al., 2015, US9057059B2—cited previously), Beibi et al (Beibi et al., 2018, WO 2018/073416—cited on the Information Disclosure Statement dated 29 March 2022), and Chen et al (Chen et al., 2018, Molecular Therapy Methods and Clinical Development—cited previously) is withdrawn in view of the amendments to claim 1, which now specifically recites “storage-stable” and “wherein the composition retains at least70% of the bacteriophage lysin upon 5 weeks of storage at 40oC.” Grallert et al., Beibi et al., and Chen et al., do not explicitly teach the utilization of HEPES as a long-term storage buffer. Said rejection has been withdrawn in view of the modified rejection below.
5. The rejection of claim 10 over Grallert et al., Biebi et al., and Chen et al. as applied to claims 1, 6-9, 11-12, and 16-17 above, and further in view of Pot et al (Pot et al., 2021, US20210030664A1—cited previously) is withdrawn in view of the amendments to claim 1, which now specifically recites “storage-stable” and “wherein the composition retains at least70% of the bacteriophage lysin upon 5 weeks of storage at 40oC.” Grallert et al., Beibi et al., and Chen et al., do not explicitly teach the utilization of HEPES as a long-term storage buffer. Said rejection has been withdrawn in view of the modified rejection below.
6. The rejection of claim 19 over Grallert et al., Biebi et al., and Chen et al. as applied to claims 1, 6-9, 11-12, and 16-17 above, and further in view of Patra et al (Patra et al., 2001, Toxicology—cited previously) is withdrawn in view of the amendments to claim 1, which now specifically recites “storage-stable” and “wherein the composition retains at least70% of the bacteriophage lysin upon 5 weeks of storage at 40oC.” Grallert et al., Beibi et al., and Chen et al., do not explicitly teach the utilization of HEPES as a long-term storage buffer. Said rejection has been withdrawn in view of the modified rejection below.
Claim Rejections - 35 USC § 103
7. 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.
8. 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.
9. Claims 1, 6-9, 11-12, and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Grallert et al (Grallert et al., 2015, US9057059B2—cited previously) and Canning et al. (Canning et al., 2005, US6979442B1—cited herein).
Regarding claims 1, 6-9, 11-12 and 16-17, drawn to a storage stable composition comprising: (i) bacteriophage lysin at a concentration of 0.2mg/mL (claim 11); (ii) a piperazine- or morpholine-containing zwitterionic buffering substance, which is HEPES (claim 1), and a concentration of about 20mM (claim 9), where HEPES is the sole buffering substance (claim 17); and (iii) a pharmaceutically acceptable excipient and antioxidant (claim 8), and the composition is a pharmaceutical composition (claim 16), and wherein the storage-stable composition retains at least 70% of the bacteriophage lysin upon 5 weeks of storage at 40oC, Grallert et al. teaches a chimeric peptide, which has a bacteriophage lysin as the enzymatic active domain (Column 9) for topical use (Ex. 9, Column 32, lines 5-20; Fig. 1) in a stabilizing buffer solution (column 21, lines 15-20) (also claim 6), and an excipient or carrier (column 21, line 26) (claim 1). Regarding the recitation of SEQ ID NO: 5 in claim 1, Grallert et al. continues to teaches SEQ ID NO: 15 (PRF133), which is 100% identical to SEQ ID NO: 5 (Supplemental File: 20241008_104144_us-17-631-221-5.rai, result 1). Grallert et al. continues to teach the long term stability of high concentration protein solutions in TRIS buffers at -20oC, 4oC, 25oC, and 37oC, where after 38 days at 37oC, the mixture retained 85% activity (Column 31, Example 7, lines 32-33, Table 4.1). Although 37oC is not 40oC, it is not expected that the three degree difference in storage temperature would affect the stability of the protein composition, especially given that in Example 7, the thermal stability changeover temperature (e.g. the point at which aggregation begins) was determined to be 55oC. The MPEP states, “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).” (See MPEP 2144.05.I). Additionally, Grallert et al. teaches the utilization of an antioxidant (column 21 line 4) and an excipient (column 21, lines 23-27) (claim 8). Grallert et al. continues to teach a polypeptide concentration of 0.2mg/mL (column 14, lines 53-54) (claim 11). Grallert et al. teaches that the composition may be prepared for nasal administration (column 20, lines 61-63) (claim 12). Finally, Grallert et al. teaches that the composition is a pharmaceutical composition (column 62, claim 22) (claim 16).
Grallert et al. does not teach the utilization of a piperazine -containing zwitterionic buffering substance, specifically HEPES, in a storage-stable composition (claims 1 and 17), wherein the composition retains at least 70% of the bacteriophage lysin upon 5 weeks of storage of 40oC. Additionally, Grallert et al. does not teach the utilization of 0.01-1000mM HEPES (claim 9) at a pH of 4-8 (claim 7).
Canning et al. teaches stabilized protein compositions with therapeutically effective amounts of G-CSF, in combination with a stabilizing buffer, such as HEPES, TES or TRICINE for treating and preventing infections, including mastitis, in cattle (abstract). Specifically, Canning et al. teaches, “the stabilized protein composition of the invention is a composition comprising bovine G-CSF in HEPES buffer which composition is capable of providing for an extended shelf life and storage. Preferably the HEPES buffer is in a concentration ranging from about 0.05M to about 2M. More preferably, such compositions contain are maintained at a pH of about 4.0 to about 7.5, preferably 4.0, and a temperature of less than about 40oC and preferably about 4oC. The extended shelf life and storage is in the range of from about 3 weeks to about 18 months, and preferably, is in the range of from about 6 weeks to about 1 year” (Column 5, lines 5-16). The formulations were stabilized in HEPES buffer for 9 days at 40oC. HEPES buffer provided the best stabilizing environment at this time period and temperature (See example 1, Figs. 1-6, and Tables 3-4).
Therefore, it would have been obvious to one skilled in the art prior to the effective filing date of the claimed invention to combine the teachings of Grallert et al. and Canning et al. to formulate a composition of a bacteriophage lysin in a HEPES buffer to reduce the loss of activity over time, especially at elevated temperatures as taught by Canning et al (Column 1, lines 35-39). One would be motivated to combine these teachings to arrive at the instant claims to stabilize enzymes, especially at higher temperatures to stabilize enzymes to avoid the loss of activity, especially during administration to a mammal, where body temperature is close to 40oC and pH is at physiological level, as taught by Canning et al (Column 1, lines 51-53). There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Grallert et al. and Canning et al. to formulate a composition of bacterial lysin in HEPES for long term storage at 40oC for 5 weeks, since Canning et al. teaches the storage of an enzyme at high temperature for an extended period of time in HEPES buffers (as detailed above).
10. Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Grallert et al. and Canning et al. as applied to claims 1, 6-9, 11-12, and 16-17 above, and further in view of Pot et al (Pot et al., 2021, US20210030664A1—cited previously).
The teachings of Grallert et al. and Canning et al. are discussed above and incorporated into the instant rejection.
Grallert et al. and Canning et al. do not teach the utilization of hydroxypropyl methylcellulose (HPMC) in the composition containing the bacteriophage lysin. Pot et al. teaches the most suitable biologically compatible material for production of the layers of the mucoadhesive patch, film, or hydrogel, where specifically the utilization of HPMC is as a polymer (paragraph 0020).
Therefore, it would have been obvious to one skilled in the art prior to the effective filing date of the claimed invention to combine the teachings of Grallert et al. and et al. with that of Pot et al. to formulate a composition of a bacteriophage lysin in a HEPES buffer along with HPMC to formulate the composition to be a film or hydrogel containing a biologically compatible polymer for topical use as taught by Pot et al. (paragraph 0020). One would be motivated to combine these teachings to arrive at the instant claims to produce layers of a mucoadhesive patch containing the pharmaceutical, which will also decompose after the release of the pharmaceutical as taught by Pot et al (paragraph 0020). There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Grallert et al. and Canning et al. with that of Pot et al., since Pot et al. describes successful utilization of HPMC as a polymer in pharmaceutical compositions (as detailed above).
11. Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Grallert et al. and Canning et al. as applied to claims 1, 6-9, 11-12, and 16-17 above, further in view of Patra et al (Patra et al., 2001, Toxicology—cited previously), and further in view of Beibi et al (Beibi et al., 2018, WO 2018/073416—cited on the Information Disclosure Statement dated 29 March 2022).
The teachings of Grallert et al. and Canning et al. are discussed above and incorporated into the instant rejection. Additionally, Grallert et al. teaches the addition of NaCl to the buffer composition (Column 17, claim 25).
Grallert et al. and Canning et al. do not teach the use of methionine as an antioxidant or a low pH.
Patra et al. teaches the utilization of methionine as an antioxidant, specifically as a precursor to the production of glutathione, which acts as a low molecular weight antioxidant and can be readily taken up into cells (p. 82, 2nd column, first full paragraph).
Biebi et al. teaches the utilization of the excipient, NaCl, the protein solution (Ex. 1, p. 24). Biebi et al. continues to teach a wildtype endolysin that is more active at more acidic pH’s, i.e. 5.25 or 6 (p. 11, paragraph 2, last two lines).
Therefore, it would have been obvious to one skilled in the art prior to the effective filing date of the claimed invention to combine the teachings of Grallert et al. and Canning with Patra et al. to formulate a composition of a bacteriophage lysin in an acidic HEPES buffer because some endolysins are more active at lower pH’s as taught by Biebi et al., and antioxidants, such as methionine, can act as a physiologically acceptable carrier in addition to a buffered solution as taught by Grallert et al (column 21, lines 3-5). One would be motivated to combine these teachings to arrive at the instant claims to utilize the pharmaceutical composition containing the endolysin at an optimal pH and to ensure that the composition is non-toxic to the cell or the subject being exposed thereto by utilizing an antioxidant, such as methionine, as a physiologically acceptable carrier (column 20, lines 65-67). There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Grallert et al., Canning et al., with Biebi et al. and with Patra et al., since Biebi et al. describes endolysins utilizing a low pH, and Grallert et al. describes the utilization of antioxidants in the pharmaceutical composition as a physiologically acceptable carrier (as detailed above).
Applicant’s Arguments and Examiner’s Rebuttal
The applicant traverses the previous 35 U.S.C. 103 rejection of record of claims 1, 6-9, 11-12, and 16-17 over Grallert et al., Biebi et al., and Chen et al. Additionally, the applicant traverses the previous 35 U.S.C. 103 rejection of claim 1 Grallert et al., Biebi et al., and Chen et al. and further in view of Pot et al. Lastly, the applicant traverses the 35 U.S.C. 103 rejection of Claim 19 over Grallert et al., Biebi et al., and Chen et al. and further in view of Patra et al.
The claim amendments have been addressed in the above new rejections.
First, the Applicant argues that the amended claim now recites the new limitations “storage-stable” and “wherein the composition retains at least 70% of the bacteriophage lysin upon 5 weeks of storage at 40oC,” and is therefore free of the prior art rejection. This limitation has been discussed thoroughly in the new rejections above. The applicant continues to argue that these new limitations are surprising results. However, the examiner respectfully disagrees. As the new obviousness type rejection above teaches, the combination of Grallert et al. and Canning et al. do demonstrate storage-stable protein compositions in buffers, such as HEPES (Canning et al), at high temperatures (40oC), with a retained activity after 9 days (Canning et al., discussed thoroughly above). Although 9 days is less than 35 days, the demonstration of long-term storage is still evident with this time period, since the pharmaceutical composition of Canning et al. maintained a high level of activity over water and/or other buffer formulations. Therefore, the Examiner contends that storage stability is an inherent feature of the enzyme mixture in HEPES buffer at high temperature and not a surprising result.
Second, the applicant argues that Grallert et al. is silent on storage-stable compositions. The examiner agrees with this statement; however, as the new rejection teaches above, Canning et al. teachings are utilized for both storage stability and the utilization of HEPES as a buffer.
Third, the applicant argues that the present invention took a path not seen or foreshadowed by anyone in the prior art, specifically the utilization of HEPES for high and long-term stabilization of HY-133. The examiner respectfully disagrees and has detailed this argument above and in the prior art rejection of record above. Again, Canning et al. demonstrates the long-term storage of a protein in HEPES at 40oC at physiological pH specifically for the administration of the composition to cattle for treatment, as detailed above.
The examiner does not find the arguments presented by the Applicant persuasive, and for these reasons, the rejections of record above apply.
Conclusion
12. All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CIARA A MCKNIGHT whose telephone number is (703)756-4791. The examiner can normally be reached M-F 8:00am-4:30pm.
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/CIARA A MCKNIGHT/Examiner, Art Unit 1656
/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656
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