DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment and response filed on 03/20/2026 have been received and entered into the case. Claims 9, 17-22 and 27-28 have been canceled. Claims 1-8, 10-16, 23-26, and 29-35 are pending, Claims 3-5, 8, 10-16, 23-26, and 29-35 have been withdrawn, and Claims 1-2, 6 and 7 have been considered on the merits, insofar as they read on the elected species of 150 units/ml recombinant human HAase, SEQ ID NO: 2, 10 mM phosphate buffering agent, 145 mM sodium chloride, 10 mM methionine, 0.02% w/v polysorbate 20, pH 7.0. All arguments have been fully considered.
Withdrawn Objections
Objections are withdrawn in view of applicant’s amendments.
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.
Claim 7 is 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 pre-AIA the applicant regards as the invention.
Claim 7(46), line 2, the phrase “0.02%” has no unit.
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 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 1-2, 6 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Frost et al (US 2019/0336587 A1; 11/7/2019.) in view of Adler et al (US 9,968,676 B2; 5/15/2018.).
The instant claims recite a recombinant human hyaluronidase (HAase) formulation, comprising a recombinant human HAase, a buffering agent, a stabilizer and a nonionic surfactant, wherein the recombinant human HAase has an enzyme activity of 45 units/ml to 4500000 units/ml; the buffering agent has a concentration of 5 to 50 mM, the buffering agent is a phosphate buffering agent; the stabilizer comprises methionine, the concentration of the methionine is 5 to 50 mM, the stabilizer further comprises any one of (a)-(d): (a) 30 to 250 mM sodium chloride; (b) 30 to 250 mM sodium chloride and 10 to 250 mM trehalose or sucrose; (c) 150 to 300 mM mannitol, and 10 to 250 mM trehalose or sucrose, or 30 to 250 mM sodium chloride; (d) 150 to 300 mM mannitol, 30 to 250 mM sodium chloride, and 10 to 250 mM trehalose or sucrose; the nonionic surfactant has a concentration of 0.01% to 0.1% (w/v); and the formulation has a pH of 5.0 to 8.0.
Frost teaches a formulation comprising a modified soluble hyaluronidase, NaCl (a stabilizer), methionine (a stabilizer), phosphate buffer, polysorbates (a nonionic surfactant), and a pH of 7 (para 0388), wherein the hyaluronidase is provided at or about 150 U/ml (para 0422), NaCl is provided in an amount of about 100 mM – 150 mM, e.g., about 130 mM (para 0389), polysorbates are present in an amount of 0.02% (para 0388), and the soluble hyaluronidase is a recombinant human PH20 SEQ ID NO. 48 (a recombinant human HAase has an amino acid sequence as shown in SEQ ID NO. 2, see Search results dated 12/17/2025, 20251217_154907_us-18-260-079a-2.rag, AXR75981, also published as WO2009128917-A2) (para 0132).
Frost does not teach the claimed concentration of phosphate buffer (claims 1 and 7), the claimed concentrations of NaCl and methionine (claims 6 and 7), and the polysorbate is polysorbate 20 (claim 7).
However, Frost does teach the formulation contains minor amounts of buffering agents (para 0387) including phosphate buffer (para 0388), about 100 mM – 150 mM NaCl, e.g., about 130 mM NaCl (an amount that encompasses or is close to the claimed amount of NaCl) (para 0389), methionine (para 0388), and 0.02% polysorbates (para 0388). Frost does teach the concentration of the pharmaceutically active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect (para 0393).
In addition, Adler teaches a formulation comprising hyaluronidase, a buffering agent, a stabilizer, and a nonionic surfactant (Abstract), wherein the stabilizer includes 10 mM methionine (col.5 line 28-29), suitable examples of pharmaceutically acceptable surfactants include polysorbate 20 (col.5 line 8), and the concentration of the nonionic surfactant is 0.02% w/v (col.5 line 50).
Thus, before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to incorporate an optimized concentration of phosphate buffer, NaCl, methionine, and polysorbate 20, since Frost discloses that phosphate buffer, NaCl, methionine, and polysorbate are included in a standard stabilized formulation comprises a recombinant human hyaluronidase, and that the percentage of active compound is highly dependent on the specific nature as well as the activity of the compound and the needs of a subject (para 0387), and Adler discloses specific amounts of methionine and polysorbate 20 included in a formulation comprises hyaluronidase. Generally, differences in concentration will not support patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. (MPEP 2144.05 II) Moreover, before the effective filing date of the claimed invention, one of ordinary skill in the art would have been motivated by the cited reference and routine practice to incorporate an optimized concentration of phosphate buffer, NaCl, methionine, and polysorbate 20 with a reasonable expectation for successfully obtaining a formulation.
Response to Arguments
Applicant argues that Frost fails to teach or suggest every element of the claimed formulation, that Frost consistently discloses hyaluronidase conjugated to a polymer, by contrast, the claimed formulation comprises a native hyaluronidase, which is not conjugated to any polymer, and that Frost provides no specific formulation examples, no stability data, no enzyme-activity data, and no guidance for selecting particular combinations of components to achieve a stable hyaluronidase formulation.
These arguments are not found persuasive. Applicant is reminded that preferred embodiments are not the only teaching of a reference. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). In the instant case, Frost does teach the hyaluronidase is a recombinant human PH20 SEQ ID NO. 48 (para 0132), a recombinant human HAase has an amino acid sequence as shown in SEQ ID NO. 2, see Search results dated 12/17/2025, 20251217_154907_us-18-260-079a-2.rag, AXR75981, also published as WO2009128917-A2. In addition, Frost does teach the standard stabilized formulation is formulated with one or more of NaCl, methionine, a phosphate buffer, polysorbates, and has a pH of 7 (para 0388).
Applicant argues that Adler does not mention phosphate buffer anywhere in its disclosure, that Adler teaches away from the use of phosphate buffer, that neither Frost nor Adler provides any guidance that would lead a PHOSITA to select a phosphate buffer, nor does either reference disclose that choosing a phosphate buffer would improve the stability of a hyaluronidase formulation, that a PHOSITA relying on Adler's experimental data would avoid using NaCl as a stabilizer.
These arguments are not found persuasive because Adler is relied upon to demonstrate the concentration of methionine and polysorbate 20. Adler is not relied upon to demonstrate phosphate buffer or NaCl. Frost does teach the formulation comprises a hyaluronidase, NaCl, methionine, phosphate buffer, and polysorbates. Furthermore, Frost does teach the formulation contains buffering agents including phosphate buffer, about 100 mM – 150 mM NaCl (which encompasses the claimed NaCl concentration), and 0.02% polysorbates, wherein the concentration of the pharmaceutically active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect, and the percentage of active compound is highly dependent on the specific nature as well as the activity of the compound and the needs of a subject. Finally, Adler does teach a formulation comprises hyaluronidase, a buffering agent, a stabilizer, and a nonionic surfactant, wherein the stabilizer includes 10 mM methionine, suitable examples of pharmaceutically acceptable surfactants include polysorbate 20, and the concentration of the nonionic surfactant is 0.02% w/v. It is noted that “disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or non-preferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).” (MPEP 2123) Further, “the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).” (MPEP 2141.02)
Applicant argues that a PHOSITA cannot "optimize" concentrations of a combination that the prior art neither enables nor suggests in the first place, and that applicant argues unexpected results.
These arguments are not found persuasive because Frost does teach the formulation comprises a hyaluronidase, NaCl, methionine, phosphate buffer, and polysorbates. Furthermore, Frost does teach the formulation contains buffering agents including phosphate buffer, about 100 mM – 150 mM NaCl (which encompasses the claimed NaCl concentration), and 0.02% polysorbates, wherein the concentration of the pharmaceutically active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect, and the percentage of active compound is highly dependent on the specific nature as well as the activity of the compound and the needs of a subject. Therefore, a skill in the art would have been motivated by the cited reference to incorporate an optimized amount of the claimed components. In addition, differences in concentration will not support patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. (MPEP 2144.05 II) Applicant has failed to provide evidence demonstrating the criticality of the claimed concentrations. Finally, evidence relied upon should establish that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. In the instant case, there was no comparison of the claimed invention with the closest prior art, and thereby lack of basis for judging the practical significance of data with regard to the disclosed unexpected results. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. (MPEP 716.02).
Conclusion
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 extension fee 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.
Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN Y FAN whose telephone number is (571)270-3541. The examiner can normally be reached on M-F 7am-4pm.
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/Lynn Y Fan/
Primary Examiner, Art Unit 1759
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