DETAILED CORRESPONDENCE
Notice of AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Application Status
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/23/2025 has been entered.
Applicants’ amendment to the claims filed on 05/11/2026 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
Claims 41-45, 47-48, 51, 54-57, 59-60 and 63-73 are pending.
Election/Restrictions
Applicant's election with traverse of the species corresponding to positions 344, 347, 348, 352, 355 and 359, with reference to amino acids 38-332 and 375-468 of SEQ ID NO: 6, in the reply filed on 05/11/2026 is acknowledged. The traversal is on the ground(s) that examination of the genus would not be unduly burdensome, as it is directed to variations within a single sequence framework. This is not found persuasive because as stated in the Restriction Requirement mailed on 03/23/2026, each species of mutations is a unique structure with unique function requiring unique searches.
The requirement is still deemed proper and is therefore made FINAL.
Claims 47-48, 54-57, 59-60, 63 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 05/29/2026.
Claims 41-45, 51, 64-73 will be examined to the extent they read on the elected species corresponding to positions 344, 347, 348, 352, 355 and 359.
Information Disclosure Statement
The IDS filed on 12/23/2025 has been considered by the examiner and a copy of the Form PTO/SB/08 is attached to the office action.
Withdrawal of Previous Rejections
The rejections of claim 40 under 35 U.S.C. 112(b) and (d) are withdrawn in view of the cancelation of said claim.
The written description rejection of claims 24 and 40-63 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph is withdrawn in view of the cancelation of said claims.
The scope of enablement rejection of claims 24 and 40-63 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph is withdrawn in view of the cancelation of said claims.
The rejection of claims 24 and 40-63 under 35 U.S.C. 101 for lack of utility is withdrawn in view of the cancelation of said claims and upon further consideration.
Specification/Informalities
The specification is objected to because the amended sequence listing incorporation statement at p. 5, lines 12-15 of the specification filed 03/05/2025 does not comply with the requirements for a sequence listing, which require the size of the XML file to be listed in bytes (not kilobytes). See MPEP 2422.03. and see MPEP 2422.03(a) for additional information pertaining to EFS-Web submission of sequence listings.
New Rejections
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 41-45, 51, 64-73 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
A. Claim 64 (claims 41-45, 51, 65-73 dependent therefrom) recite “polypeptide comprising amino acids 38-332 of SEQ ID NO: 6 and 375-468 of SEQ ID NO: 6” in part (i) and “the polypeptide comprises an amino acid replacement…located at amino acid position…with reference to amino acids 38-468 of SEQ ID NO: 6”. It is unclear as to how the claimed polypeptide can simultaneously comprise amino acids 3-433 of SEQ ID NO: 6 and comprise an amino acid replacement of the recited position(s) of amino acids 3-433 of SEQ ID NO: 6. It is suggested that applicant clarify the meaning of the claim or alternatively, in part (ii) recite something like: the polypeptide further comprises.
B. Claims 69-70 depend from claim 64 and thus, said claims incorporate all limitations of claim 64.
Claims 69-70 are unclear in requiring the claimed polypeptide to have a hyaluronidase activity that is at least 40% of a hyaluronidase activity with respect to a reference polypeptide consisting of amino acids 38-468 of SEQ ID NO: 6, and also requiring an additional amino acid replacement located at an amino acid position that confers less than 40% hyaluronidase activity when the amino acid position that confers less than 40% hyaluronidase activity is replaced alone in a polypeptide consisting of amino acids 38-468 of SEQ ID NO: 6 and the amino acid replacement. It is suggested that applicant clarify the meanings of the claims.
C. Claim 64 recites that the substitutions are selected from amino acid replacement is located at amino acid position 333, 335, 336, 337, 338, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 352, 353, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 366, 370, 373, 374, or any combination thereof, with reference to amino acids 38-468 of SEQ ID NO: 6.
It is noted, SEQ ID NO: 6 is the PH20 full length, precursor protein having 509 amino acids in length. SEQ ID NO: 3, as recited throughout the specification, is the mature PH20 polypeptide having 447 amino acids in length, e.g. lacking amino acids 1-35 of SEQ ID NO: 6 (See paragraph 0245 of PG-Pub) and amino acids 483-509 of SEQ ID NO: 6 – a sequence alignment is provided below for convenience, wherein Qy = SEQ ID NO: 3 and Db = SEQ ID NO: 6.
GenCore version 6.5.2
Copyright (c) 1993 - 2026 Biocceleration Ltd.
OM protein - protein search, using sw model
Run on: July 13, 2026, 19:13:49 ; Search time 1 Seconds
(without alignments)
0.228 Million cell updates/sec
Title: US-19-071-092-3
Perfect score: 2403
Sequence: 1 LNFRAPPVIPNVPFLWAWNA..........VCIDAFLKPPMETEEPQIFY 447
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 1 seqs, 509 residues
Total number of hits satisfying chosen parameters: 1
Minimum DB seq length: 0
Maximum DB seq length: inf
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 50 summaries
Database : US-19-071-092-6.fasta:*
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 2403 100.0 509 1 US-19-071-092-6 PH20 POLYPEPTIDE V
ALIGNMENTS
RESULT 1
US-19-071-092-6
Query Match 100.0%; Score 2403; DB 1; Length 509;
Best Local Similarity 100.0%;
Matches 447; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 LNFRAPPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSPRINATGQGVTIFYVDR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 36 LNFRAPPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSPRINATGQGVTIFYVDR 95
Qy 61 LGYYPYIDSITGVTVNGGIPQKISLQDHLDKAKKDITFYMPVDNLGMAVIDWEEWRPTWA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 96 LGYYPYIDSITGVTVNGGIPQKISLQDHLDKAKKDITFYMPVDNLGMAVIDWEEWRPTWA 155
Qy 121 RNWKPKDVYKNRSIELVQQQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLGKLLRPNHL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 156 RNWKPKDVYKNRSIELVQQQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLGKLLRPNHL 215
Qy 181 WGYYLFPDCYNHHYKKPGYNGSCFNVEIKRNDDLSWLWNESTALYPSIYLNTQQSPVAAT 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 216 WGYYLFPDCYNHHYKKPGYNGSCFNVEIKRNDDLSWLWNESTALYPSIYLNTQQSPVAAT 275
Qy 241 LYVRNRVREAIRVSKIPDAKSPLPVFAYTRIVFTDQVLKFLSQDELVYTFGETVALGASG 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 276 LYVRNRVREAIRVSKIPDAKSPLPVFAYTRIVFTDQVLKFLSQDELVYTFGETVALGASG 335
Qy 301 IVIWGTLSIMRSMKSCLLLDNYMETILNPYIINVTLAAKMCSQVLCQEQGVCIRKNWNSS 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 336 IVIWGTLSIMRSMKSCLLLDNYMETILNPYIINVTLAAKMCSQVLCQEQGVCIRKNWNSS 395
Qy 361 DYLHLNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSEKFYCSCYSTLSCKEKADVKDTDAV 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 396 DYLHLNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSEKFYCSCYSTLSCKEKADVKDTDAV 455
Qy 421 DVCIADGVCIDAFLKPPMETEEPQIFY 447
|||||||||||||||||||||||||||
Db 456 DVCIADGVCIDAFLKPPMETEEPQIFY 482
There are two separate items that make the claims indefinite in reference to claim 64, and all dependent claims therefrom.
First, given the mature form of the polypeptide is SEQ ID NO: 3, this would mean that SEQ ID NO: 6 would not comprise amino acids 1-35 and 483-509. However, claim 64 recites SEQ ID NO: 6 does not comprise amino acids 1-37 and 469-509. It is entirely unclear if these are the intended positions because they are never recited throughout the specification. Rather, it is clear that the mature form of SEQ ID NO: 6 would lack amino acids 1-35 and 483-509, rather than the positions recited as noted and recited in claim 64. Clarification is required here.
Second, this then leads to the second point of indefiniteness and that is it is unclear if the positions for replacement recited in claim 64, e.g. 333, 335, 336, 337, 338, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 352, 353, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 366, 370, 373, 374 of SEQ ID NO: 6 are truly the position for SEQ ID NO: 6 or really positions intended for the mature form of SEQ ID NO: 3. This is because every single amino acid replacement position recited in the specification is referenced to SEQ ID NO: 3 not SEQ ID NO: 6 – See For example, the Tables 3 and 5, where the positions are expressly stated as referring and being relative to SEQ ID NO: 3. See paragraph 0280 (PG-Pub) which states: “Exemplary amino acid replacements at any of the above corresponding positions are set forth in Table 3. Reference to the corresponding amino acid position in Table 3 is with reference to positions set forth in SEQ ID NO:3.” While it clear this paragraph also stipulates that the positions can be understood to be corresponding positions (e.g “It is understood that the replacements can be made in the corresponding position in another PH20 polypeptide by alignment therewith with the sequence set forth in SEQ ID NO:3 (see e.g., FIGS. 1 and 2 ), whereby the corresponding position is the aligned position.”); while the claim stipulates that the positions are in reference to SEQ ID NO: 6, given that the specification is drawn entirely to positions of SEQ ID NO: 3, it is unclear if the positions recited are clearly drawn to positions of SEQ ID NO: 6 or 3. If it is to be assumed that the positions are intended to be drawn to SEQ ID NO: 6, then the corresponding positions in SEQ ID NO: 3 would be subtracted by 35 amino acids, e.g. position 333 of SEQ ID NO: 6 is position 298 of SEQ ID NO: 3 (See alignment above). However, and for example, position 357 of SEQ ID NO: 6, which is position 322 of SEQ ID NO: 3, and position 364 of SEQ ID NO: 6, which is position 329 of SEQ ID NO: 3, are not found in Table 3, which is the table demonstrating replacements resulting in at least 40% hyaluronidase activity.
As such, it is unclear if the positions in claim 64 are positions truly intended for SEQ ID NO: 6 or were actually meant to reference the positions in SEQ ID NO: 3.
Clarification is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
A. Written Description
Claims 41-45, 51, 64-73 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP 2163.II.A.3.(a).ii) states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
MPEP § 2163 further states that “[s]atisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’ Such correlations may be established ‘by the inventor as described in the specification,’ or they may be ‘known in the art at the time of the filing date.’"
Claims 41-45, 51, 64-73 are drawn in relevant part to a polypeptide comprising amino acids 38-332 of SEQ ID NO: 6 and amino acids 375-468 of SEQ ID NO: 6, wherein the polypeptide (i) does not comprise 1-37 of SEQ ID NO: 6 and amino acids 469-509 of SEQ ID NO: 6 and (ii) comprises an amino acid replacement, wherein the polypeptide comprising the amino acid replacement has a hyaluronidase activity that is at least 40% of a hyaluronidase activity with respect to a reference polypeptide consisting of amino acids 38-468 of SEQ ID NO: 6 and wherein the amino acid replacement is located at amino acid positions 344, 347, 348, 352, 355 and 359 or any combination thereof, with reference to amino acids 38-468 of SEQ ID NO: 6. In view of the recitation of “at least one amino acid replacement”, the claim is interpreted as included any number of additional mutations drawn to a huge and variable genus of polypeptides which all require the requisite structure and function of at least 40% hyaluronidase activity; and as such the structure and function of the polypeptide are nearly unlimited.
In this case, the specification discloses an actual reduction to practice of the following representative species of the genus of “polypeptides” as encompassed by the claims, i.e. a PH20 polypeptide, comprising SEQ ID NO: 3 having at least 40% hyaluronidase activity with a single point mutation in positions corresponding to the positions listed in Table 3. Notably, each and every one is a single point mutation. Other than the above disclosed species there is no other drawings or structural formulas of the large and variable genus of polypeptides in terms of structure and function as encompassed by the claims. Further or note, is the fact that some mutations at the very same positions inactivate PH20 while others have at least 40% hyaluronidase activity. For example, position 3 of SEQ ID NO:3 (which would be position 38 of SEQ ID NO: 6) having an AGKPTV substitution results in inactive mutations; while those that are EHLY in the exact same position result in at least 40% hyaluronidase activity. It is noted, several of these would be considered conservative to one another, e.g. the expectation is that if you made, for example, Leucine substitution that results in at least 40% activity, why then would a similar substitution of Valine result in an inactive mutant. This is just single example of the complexity and unpredictability of the claimed genus of PH20 polypeptides being claimed.
Regarding the level of skill and knowledge in the art of amino acid modification, MPEP 2144.08.II.A.4.(c) states, "[i]n the area of biotechnology, an exemplified species may differ from a claimed species by a conservative substitution ("the replacement in a protein of one amino acid by another, chemically similar, amino acid... [which] is generally expected to lead to either no change or only a small change in the properties of the protein." Dictionary of Biochemistry and Molecular Biology 97 (John Wiley & Sons, 2d ed. 1989)). The effect of a conservative substitution on protein function depends on the nature of the substitution and its location in the chain. Although at some locations a conservative substitution may be benign, in some proteins only one amino acid is allowed at a given position. For example, the gain or loss of even one methyl group can destabilize the structure if close packing is required in the interior of domains. James Darnell et al., Molecular Cell Biology 51 (2d ed. 1990)."
In the Federal Circuit decision, Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337 (Fed. Cir. 2021), the courts found that for broad claims to a nucleic acid encoding a chimeric T cell receptor with a functional requirement to bind a target, “the written description must demonstrate that the applicant made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus”. In the instant case, the claims are drawn to polypeptide of unlimited structure and function, and the specification does not disclose sufficient structural features in the claimed polypeptide sequence associated with any activity to allow an ordinary artisan to distinguish which multiple mutated sequences will result in polypeptides of any activity. While a person skilled in the art might be able to embark on their own research program to find suitable multiply modified polypeptides, the four corners of the written description do not demonstrate possession of such. This analysis is consistent with AbbVie Deutschland GmbH v. Janssen Biotech, Inc., 759 F.3d 1285, 1300 (Fed. Cir. 2014) which required an inventor to show “that one has truly invented the genus, i.e. that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus”.
Given that the specification discloses only a relative few representative species of single amino acid mutations at each of positions 344, 347, 348, 352, 355 and 359 with reference to amino acids 38-468 of SEQ ID NO: 6 (or the positions refer to positions corresponding SEQ ID NO: 3, see above 112(b)), the specification fails to disclose even a single representative species of the claimed polypeptide, and there is a very high level of unpredictability in the art of amino acid modification, the specification is considered to be insufficient to describe the claimed genus of polypeptides. In this case, the specification at best describes a research plan for making, testing, and identifying those species that are encompassed by the claimed genus of polypeptides, however, a plan for making the claimed invention is not sufficient to show possession at the time of filing. One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus, and thus, that the applicant was not in possession of the recited genus.
In the en banc decision of Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F.3d 1336, 94 USPQ2d 1161 (Fed. Cir. 2010), the court reaffirmed CAFC court decisions of the past by reiterating the purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification. Rochester, 358 F.3d at 920 (Fed. Circ. 1997) (quoting Reiffin v. Microsoft Corp., 214 F.3d 1342, 1345 [54 USPQ2d 1915] (Fed. Cir. 2000)).”
And finally, the courts established a clear nexus between structure-function correlation requirement for the showing of possession of an invention with regard to written description (or lack thereof) and limited disclosure/species. See Novozymes A/S v. DuPont Nutrition Biosciences APS, 723 F.3d 1336 (Fed. Cir. 2013):
A patent, however, “is not a reward for the search, but compensation for its successful conclusion.” Ariad, 598 F.3d at 1353 (quoting University of Rochester, 358 F.3d at 930 n.10). For that reason, the written description requirement prohibits a patentee from “leaving it to the . . . industry to complete an unfinished invention.” Id.
For these reasons, it is the examiner’s position that the specification fails to adequately describe the claimed invention, of combined substitutions of PH20 polypeptide comprising SEQ ID NO: 6 resulting in at least 40% hyaluronidase activity.
B. Scope of Enablement
Claims 41-45, 51, 64-73 are rejected under 35 U.S.C. 112(a) because the specification, while enabling for a PH20 polypeptide having hyaluronidase activity with a single point mutation in positions corresponding to positions as listed in claim 64: 333, 335, 336, 337, 338, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 352, 353, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 366, 370, 373 or 374, specifically those corresponding substitutions listed in claim 64 and Table 3 for each position, referencing amino acids 38-468 of SEQ ID NO:6 (noting the 112(b), part C, rejection above which needs clarification) does not reasonably provide enablement for all PH20 polypeptides having any number of combined substitutions as encompassed by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
“The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue.” In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976). Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)) as follows: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP § 2164.01(a). The Factors considered to be most relevant to the instant rejection are addressed in detail below.
The breadth of the claims: Claims 44-48, 57, 60, 62, and 66-77 are drawn in relevant part to a polypeptide comprising amino acids 38-468 of SEQ ID NO: 6, wherein the polypeptide (i) does not comprise 1-37 of SEQ ID NO: 6 and amino acids 469-509 of SEQ ID NO: 6 and (ii) comprises an amino acid replacement, wherein the polypeptide comprising the amino acid replacement has a hyaluronidase activity that is at least 40% of a hyaluronidase activity with respect to a reference polypeptide consisting of amino acids 38-468 of SEQ ID NO: 6 and wherein the amino acid replacement is located at amino acid position 69, 70, 166, 309, 313, and 320 or any combination thereof, with reference to amino acids 38-468 of SEQ ID NO: 6. In view of the recitation of “at least one amino acid replacement”, the claim is interpreted as included any number of additional mutations resulting in huge genus of unpredictable outcomes (for example, and as noted above, position 3 of SEQ ID NO:3 (which would be position 38 of SEQ ID NO: 6) having an AGKPTV substitution results in inactive mutations; while those that are EHLY in the exact same position result in at least 40% hyaluronidase activity. It is noted, several of these would be considered conservative to one another, e.g. the expectation is that if you made, for example, Leucine substitution that results in at least 40% activity, why then would a similar substitution of Valine result in an inactive mutant. This is just single example of the complexity and unpredictability of the claimed genus of PH20 polypeptides being claimed resulting in unpredictable outcomes. This says nothing about the unpredictability of combined mutations which likely are even more complex and unpredictable.
The state of the prior art; The level of one of ordinary skill; and The level of predictability in the art: As noted above, the structure and function of the claimed polypeptide is very large and very unpredictable.
Regarding the level of skill and knowledge in the art of amino acid modification, MPEP 2144.08.II.A.4.(c) states, "[i]n the area of biotechnology, an exemplified species may differ from a claimed species by a conservative substitution ("the replacement in a protein of one amino acid by another, chemically similar, amino acid... [which] is generally expected to lead to either no change or only a small change in the properties of the protein." Dictionary of Biochemistry and Molecular Biology 97 (John Wiley & Sons, 2d ed. 1989)). The effect of a conservative substitution on protein function depends on the nature of the substitution and its location in the chain. Although at some locations a conservative substitution may be benign, in some proteins only one amino acid is allowed at a given position. For example, the gain or loss of even one methyl group can destabilize the structure if close packing is required in the interior of domains. James Darnell et al., Molecular Cell Biology 51 (2d ed. 1990)."
Here, while the ordinately skill level is high, one cannot reasonably predict the outcome of the combination of mutations being claimed, despite the fact PH20 is an extremely well characterized enzyme – see for example, Arming et al. (European J. Biochem., 1997 – cited on IDS from 05/25/2025). While conserved residues could be ascertained, for example, with multiple sequence alignments, the nature of the substitutions as noted above and as demonstrated in the instant specification suggests that there making complex substitutions as currently claimed will not be predictable or easy without significant trial and error.
The amount of direction provided by the inventor and The existence of working examples: The specification discloses the following working examples of polypeptides of any function, i.e. a PH20 polypeptide having hyaluronidase activity with a single point mutation in positions corresponding to positions 333, 335, 336, 337, 338, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 352, 353, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 366, 370, 373, 374, of amino acids 38-468 of SEQ ID NO: 6; however as noted, it is not as straight forward because when one compares Tables 3 and 5, it is noted, most of the claimed substitutions results either in completely inactive PH20 polypeptides or those having at least 40% hyaluronidase activity. Thus, other than these working examples and specifically the substitutions as stipulated in Table 3, the specification fails to disclose any other working examples of polypeptides having multiple replacements of any activity as encompassed by the claims.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure: In the Federal Circuit decision of Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149, 1156 (Fed. Cir. 2019), the court stated that “the key enablement question is whether a person of ordinary skill in the art would know, without undue experimentation, which [species] would be effective….because of the many thousands of [species] which need to be screened for…efficacy, the quantity of experimentation needed is large and weighs in favor of non-enablement.” In the instant case, the number is not thousands but at least 1049 different polypeptides, and as such, the quantity of experimentation would be many orders of magnitude more than that in Idenix.
While methods for modifying the amino acid sequence of a polypeptide were known before the effective filing date, it was not routine in the art to screen by a trial and error process for all polypeptides of any activity with respect to a reference polypeptide comprising amino acids 38-468 of SEQ ID NO: 6 as broadly encompassed by the claims.
In view of the overly broad scope of the claims, the lack of guidance and working examples provided in the specification, the high level of unpredictability, and the state of the prior art, undue experimentation would be necessary for a skilled artisan to make and use the entire scope of the claimed invention. Applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
C. New Matter
Claims 41-45, 51, 64-73 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
MPEP § 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims”. See also MPEP 714.02. MPEP § 2163.II.A.3.(b) further states, “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112, para. 1, as lacking adequate written description”. According to MPEP § 2163.I.B, “While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure” and “The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117”.
There are two different New Matter issues:
A. Claims 41-45, 51, 64-73 recite specific combinations of amino acid replacements. Applicant fails to show support for the specific combinations of amino acid replacements as recited in claims 41-45, 51, 64-73. While the original application discloses single amino acid variants of most of the amino acids of the sequence of amino acids and generically discloses “combinations of modifications” and “one or more amino acid replacements”, there is no apparent descriptive support for the specific combinations recited in claims 41-45, 51, 64-73 in the original application as filed. In the absence of descriptive support, the recitation of these specific combinations is considered to introduce new matter into the claims.
B. The claims recite a polypeptide comprising amino acids 38-332 of SEQ ID NO: 6 and amino acids 375-468 of SEQ ID NO: 6, wherein the polypeptide does not comprise amino acids 1-37 of SEQ ID NO: 6 and amino acids 469-509 of SEQ ID NO: 6. However, nowhere in the specification are amino acids 38-332 and 375-468 ever recited, suggesting, there could be some sort of deletion between amino acids 333 and 3748. In addition, while the specification suggests deletion of the signal sequence, this is amino acids 1-35 of SEQ ID NO: 6, not 1-37 as currently claimed (See paragraphs 0132 and 0245, PG-Pub: “For example, the human PH20 mRNA transcript is normally translated to generate a 509 amino acid precursor protein (SEQ ID NO:6) containing a 35 amino acid signal sequence at the N-terminus (amino acid residue positions 1-35 of SEQ ID NO: 6”). With regard to the C-terminus truncation, the specification also not support anywhere the truncation from 469-509. Rather, for example in paragraph 0256 (PG-Pub), noting the removal of C-terminal amino acids results in soluble form of the protein, it is located from amino acids 491-509 “thus, the literature reports that a GPI-anchor attachment signal sequence of human PH20 is located at amino acid positions 491-509 of the precursor polypeptide set forth in SEQ ID NO:6, and the ω-site is amino acid position 490. Thus, in this modeling of human PH20, amino acids 491-509 are cleaved following transport to the ER and a GPI anchor is covalently attached to the serine residue at position 490.” – See paragraph 0256. So there is support for truncation from 491-509 but not necessarily 469-509. Or, at paragraph 0264, “In particular, a soluble human PH20 polypeptide is a polypeptide that is truncated after amino acid 482 of the sequence set forth in SEQ ID NO:6.”; thus, there is support from truncation of amino acids 483-509 but not necessarily 469-509.
Thus, for all of these different reasons, the claims are rejected as comprising New Matter.
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.
Claims 41-45, 51, 64-73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 32-39, 41-43, and 45-66 of copending Application No. 19/071055. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 32-39, 41-43, and 45-66 of the ‘055 application are drawn to a polypeptide comprising amino acid sequence 38-468 of SEQ ID NO: 6, wherein the polypeptide does not comprise amino acids 1-37 of SEQ ID NO : 6 and amino acids 469-509 of SEQ ID NO: 6 and comprises an amino acid replacement wherein the polypeptide comprising the amino acid replacement has a hyaluronidase activity that is at least 40% of a hyaluronidase activity with respect to a reference polypeptide consisting of amino acids 38-468 of SEQ ID NO: 6, and wherein the amino acid replacement is located at amino acid position 38, 40, 43, 44, 46, 47, 49, 50, 55, 57, 58, 59, 61, 62, 63, 70, 71, 72, 74, 76, 77, 78, 80, 81, 82, 83, 84, 85, 86, 87, 89, 93, 95, 96, 98, 102, 104, 105, 106, 107, 108, 109, 110, 112, 114, 115, 116, 117, 118, 119, 120, 121, 126, 128, 129, 131, 132, 133, 134, 137, 140, 141, 173, 176, 177, 178, 180, 181, 182, 184, 185, 187, 188, 189, 191, 192, 193, 194, 195, 196, 197, 199, 200, 201, 202, 204, 241, 243, 244, 250, 251, 252, 254, 255, 256, 257, 259, 265, 266, 267, 269, 270, 272, 273, 274, 275, 298, 300, 301, 302, 304, 305, 306, 307, 308, 309, 311, 313, 315, 322, 323, 325, 326, 329, 332, 333, 335, 336, 337, 338, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 352, 353, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 366, or any combination thereof, with reference to amino acids 38-468 of SEQ ID NO: 6.
Instant SEQ ID NO: 6 and SEQ ID NO: 6 of the ‘055 application are 100% identical and the positions as claimed in the ‘055 overlap in scope directly with the claimed positions of 333, 335, 336, 337, 338, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 352, 353, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 366, 370, 373, 374. In addition, the overlapping positions must also result in polypeptides having at least 40% hyaluronidase activity.
As such, the claims of the ‘055 application are taken as anticipatory over the instant claims.
Claims 41-45, 51, 64-73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-9, 11-13, and 15-36 of U.S. Non-provisional Application No. 19/550,132. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1, 7-9, 11-13, and 15-36 of the ‘132 application recite a polypeptide comprising amino acids 3-433 of SEQ ID NO: 35, wherein the polypeptide does not comprise amino acids 1-37 of SEQ ID NO: 6, wherein the polypeptide does not comprise amino acids 469-509 of SEQ ID NO: 6, and wherein the polypeptide comprises at least one amino acid replacement located at amino acid position 3, 5, 8, 9, 11, 12, 14, 15, 20, 22, 23, 24, 26, 27, 28, 35, 36, 37, 39, 41, 42, 43, 45, 46, 47, 48, 49, 50, 51, 52, 54, 58, 60, 61, 63, 67, 69, 70, 71, 72, 73, 74, 75, 77, 79, 81, 82, 83, 84, 85, 86, 91, 93, 94, 96, 97, 98, 99, 102, 105, 106, 138, 141, 142, 143, 145, 146, 147, 149, 150, 152, 153, 154, 156, 157, 158, 159, 160, 161, 162, 164, 165, 166, 167, 169, 206, 208, 209, 215, 216, 217, 219, 220, 221, 222, 224, 230, 231, 232, 234, 235, 237, 238, 239, 240, 263, 265, 266, 267, 269, 270, 271, 272, 273, 274, 276, 278, 279, 280, 287, 288, 290, 291, 294, 297, 298, 300, 301, 302, 303, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 317, 318, 320, 321, 323, 324, 325, 326, 327, 328, 331, 335, 338, 339, 342, 343, 348, 351, 353, 356, 359, 360, 369, 373, 376, 379, 381, 383, 385, 387, 388, 391, 393, 394, 395, 396, 397, 398, 399, 403, 404, 405, 406, 409, 410, 412, 414, 415, 419, 420, 422, 425, 428, 432, 433, or any combination thereof, with reference to amino acids 3- 433 of SEQ ID NO: 35. The dependent claims of the ‘132 application further limit the polypeptide to one having a hyaluronidase activity that is at least 40% of a hyaluronidase activity with respect to a reference polypeptide consisting of SEQ ID NO: 3.
The positions in SEQ ID NO: 35 differ by those of instant SEQ ID NO: 6 by adding 35 to each position (e.g. SEQ ID NO: 35 does not have amino acids 1-35 of SEQ ID NO: 6). Alternatively, the instant positions as claimed in claim 64 correspond to those of SEQ ID NO: 35 by subtracting 35, thus rendering positions as claimed compared to SEQ ID NO: 35 as: 298, 300, 301, 302, 303, 306 307, 308, 309, 310 311, 312, 313, 314, 315, 317, 318, 320, 321, 322, 323, 324, 326, 326, 327, 328, 329, 331, 335, 338, 339.
As such, the recites positions necessarily overlap with the instant positions and the claims of the ‘132 application are taken as anticipatory over the instant claims.
Claims 41-45, 51, 64-73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-9, 11-13, and 15-36 of U.S. Non-provisional Application No. 19546132. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘132 application recite a nucleic acid product comprising (interpreted as encoding) an amino acid sequence of amino acids 38-376 of SEQ ID NO: 6 and having a substitution of amino acid 341 with A, C, H, I, L, V, W, Y, D, E or S. Addition substitutions are at positions 342, 343, 344, 345, 347, 348, 349, 352, 354, 355, 356 and 359.
SEQ ID NO: 6 of the ‘132 application and instant SEQ ID NO: 6 are identical and instant claim 64 specifically recites position 341 is also modified; and also positions 333, 335, 336, 337, 338, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 352, 353, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 366, 370, 373, 374 may be modified.
It appears that the substitution of D, E or S in position 341, for example, would result in a PH20 having at least 40% hyaluronidase activity (as ascertained from Table 3, and position 306 of SEQ ID NO: 3, which would be the corresponding position as the claimed position 341).
As such, the claims of the ‘132 application are taken as anticipatory over the instant claims.
Claims 41-45, 51, 64-73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 32-39, 41-43, and 45-65 of copending Application No. 19/071264. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 32-39, 41-43, and 45-65 of the ‘264 application are drawn to a polypeptide comprising amino acid sequence 38-468 of SEQ ID NO: 6, wherein the polypeptide does not comprise amino acids 1-37 of SEQ ID NO : 6 and amino acids 469-509 of SEQ ID NO: 6 and comprises an amino acid replacement wherein the polypeptide comprising the amino acid replacement has a hyaluronidase activity that is at least 40% of a hyaluronidase activity with respect to a reference polypeptide consisting of amino acids 38-468 of SEQ ID NO: 6, and wherein the amino acid replacement is located at amino acid position 38, 40, 43, 44, 46, 47, 49, 50, 55, 57, 58, 59, 61, 62, 63, 70, 71, 72, 74, 76, 77, 78, 80, 81, 82, 83, 84, 85, 86, 87, 89, 93, 95, 96, 98, 102, 104, 105, 106, 107, 108, 109, 110, 112, 114, 115, 116, 117, 118, 119, 120, 121, 126, 128, 129, 131, 132, 133, 134, 137, 140, 141, 173, 176, 177, 178, 180, 181, 182, 184, 185, 187, 188, 189, 191, 192, 193, 194, 195, 196, 197, 199, 200, 201, 202, 204, 241, 243, 244, 250, 251, 252, 254, 255, 256, 257, 259, 265, 266, 267, 269, 270, 272, 273, 274, 275, 298, 300, 301, 302, 304, 305, 306, 307, 308, 309, 311, 313, 315, 322, 323, 325, 326, 329, 332, 333, 335, 336, 337, 338, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 352, 353, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 366, or any combination thereof, with reference to amino acids 38-468 of SEQ ID NO: 6.
SEQ ID NO: 6 from both application are 100% identical and the numbers recited in the claims that correspond to positions in SEQ ID NO: 6 directly overlap with one another (e.g. currently claimed positions 333, 335, 336, 337, 338, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 352, 353, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 366, 370, 373, 374). As such, the claims of the ‘264 application are taken as anticipatory over the instant claims.
Claims 41-45, 51, 64-73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-9, 12, 15-18, 20-37 of copending Application No. 19/551393 because the claims of the ‘393 application are drawn to a polypeptide comprising amino acids 38-468 of SEQ ID NO: 6, wherein the polypeptide does not comprise amino acids 1-37 of SEQ ID NO: 6, wherein the polypeptide does not comprise amino acids 469-509 of SEQ ID NO: 6, and wherein the polypeptide comprises at least one amino acid replacement located at amino acid position 333, 334, 335, 336, 337, 338, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 370, 371, 372, 373, and 374, or any combination thereof, with reference to amino acids 38-468 of SEQ ID NO: 6.
Instant SEQ ID NO: 6 and SEQ ID NO: 6 of the ‘393 application are 100% identical and the positions as claimed in the ‘393 overlap in scope directly with the claimed positions of 333, 335, 336, 337, 338, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 352, 353, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 366, 370, 373, 374. While the ‘393 application is silent with regard to the hyaluronidase activity, it would nonetheless be obvious that overlapping substitutions at the same position over the span of any of the 19 other amino acids would result in at least some PH20 polypeptides having at least 40% hyaluronidase activity.
Claims 41-45, 51, 64-73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-9, 11-13, 15-32 of copending Application No. 19/551420 because the claims of the ‘420 application are drawn to a polypeptide comprising amino acids 38-468 of SEQ ID NO: 6, wherein the polypeptide does not comprise amino acids 1-37 of SEQ ID NO: 6, wherein the polypeptide does not comprise amino acids 469-509 of SEQ ID NO: 6, and wherein the polypeptide comprises at least one amino acid replacement located at amino acid position 38, 40, 43, 44, 46, 47, 49, 50, 55, 57, 58, 59, 61, 62, 63, 70, 71, 72, 74, 76, 77, 78, 80, 81, 82, 83, 84, 85, 86, 87, 89, 93, 95, 96, 98, 102, 104, 105, 106, 107, 108, 109, 110, 112, 114, 115, 116, 117, 118, 119, 120,121, 126, 128, 129, 131, 132, 133, 134, 137, 140, 141, 173, 176, 177, 178, 180, 181, 182, 184,185, 187, 188, 189, 191, 192, 193, 194, 195, 196, 197, 199, 200, 201, 202, 204, 241, 243, 244, 250, 251, 252, 254, 255, 256, 257, 259, 265, 266, 267, 269, 270, 272, 273, 274, 275, 298, 300, 301, 302, 304, 305, 306, 307, 308, 309, 311, 313, 315, 322, 323, 325, 326, 329, 332, 333, 335, 336, 337, 338, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 352, 353, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 366, 370, 373, 374, 377, 378, 383, 386, 388, 391, 394, 395, 404, 408, 411,413,416,418,420,422,423,426, 428, 429, 430, 431, 432, 433, 434, 438, 439, 440, 441, 444, 445, 447, 449, 450, 454, 455, 457, 460, 463, 467, 468, or any combination thereof, with reference to amino acids 38-468 of SEQ ID NO: 6.
Instant SEQ ID NO: 6 and SEQ ID NO: 6 of the ‘420 application are 100% identical and the positions as claimed in the ‘420 overlap in scope directly with the claimed positions of 333, 335, 336, 337, 338, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 352, 353, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 366, 370, 373, 374. While the ‘420 application is silent with regard to the hyaluronidase activity, it would nonetheless be obvious that overlapping substitutions at the same position over the span of any of the 19 other amino acids would result in at least some PH20 polypeptides having at least 40% hyaluronidase activity.
Claims 41-45, 51, 64-73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-9, 11-13, and 15-37 of copending Application No. 19/550136. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1, 7-9, 11-13, and 15-37 of the ‘136 application are drawn to a polypeptide comprising amino acid sequence 38-468 of SEQ ID NO: 6, wherein the polypeptide does not comprise amino acids 1-37 of SEQ ID NO : 6 and amino acids 469-509 of SEQ ID NO: 6 and comprises an amino acid replacement wherein the polypeptide comprising the amino acid replacement has a hyaluronidase activity that is at least 40% of a hyaluronidase activity with respect to a reference polypeptide consisting of amino acids 38-468 of SEQ ID NO: 6, and wherein the amino acid replacement is located at amino acid position 38, 40, 43, 44, 46, 47, 49, 50, 51, 52, 53, 54, 55, 57, 58, 59, 61, 62, 63, 70, 71, 72, 74, 76, 77, 78, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 93, 95, 96, 97, 98, 99, 102, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 126, 128, 129, 131, 132, 133, 134, 135, 137, 140, 141, 173, 176, 177, 178, 180, 181, 182, 184, 185, 187, 188, 189, 191, 192, 193, 194, 195, 196, 197, 199, 200, 201, 202, 204, 236, 241, 243, 244, 250, 251, 252, 254, 255, 256, 257, 258, 259, 260, 262, 263, 264, 265, 266, 267, 269, 270, 272, 273, 274, 275, 276, 298, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 311, 313, 315, 316, 322, 323, 325, 326, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, or any combination thereof, with reference to amino acids 38-468 of SEQ ID NO: 6.
Instant SEQ ID NO: 6 and SEQ ID NO: 6 of the ‘055 application are 100% identical and the positions as claimed in the ‘055 overlap in scope directly with the claimed positions of 333, 335, 336, 337, 338, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 352, 353, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 366, 370, 373, 374. In addition, the overlapping positions must also result in polypeptides having at least 40% hyaluronidase activity. As such, the claims of the ‘055 application are taken as anticipatory over the instant claims.
Claims 41-45, 51, 64-73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 24-26 and 28-36 of copending Application No. 18/922889. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 24-26 and 28-36 of the ‘889 application are drawn to a pharmaceutical composition comprising an amino acid sequence wherein at least 95% of the residues of the amino acid sequence are identical to the residues in an amino acid sequence selected from the group consisting of SEQ ID NO: 3 and 32-66 when the amino acid sequence is aligned at positions corresponding to the sequence selected from the group consisting of SEQ ID NO: 3 and 32-66 to maximize identical residues and wherein terminal gaps are treated as non-identical; the amino acid sequence comprises an amino acid modification at a position corresponding to position 320 with reference to amino acid positions set forth in SEQ ID NO: 3; and the modification at position 320 is a replacement selected from the group consisting of E, G, H, I, K, M, N, R, S, W, Y, L, C, P, and V; and a therapeutically active agent; wherein (a) and (b) are formulated for administration in the same composition.
It is noted, position 320 of the ‘889 application corresponds to position 355 (See sequence alignment above) of instant SEQ ID NO: 6 and as such, the claims of the ‘889 application are taken as anticipatory over the instant claims.
These are provisional nonstatutory double patenting rejections because the patentably indistinct claims have not in fact been patented.
Non-Provisional
Claims 41-45, 51, 64-73 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 12,600,959.
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-15 of the ‘959 patent recite modified A modified PH20 polypeptide comprising the amino acid sequence of amino acids 38-340 of SEQ ID NO: 6, wherein the amino acid sequence has a first amino acid substitution at a residue corresponding to position 341 of SEQ ID NO: 6. Claims 2-14 recites positions 342, 343, 344, 345, 347, 348, 349, 352, 353, 354, 355, 359 are also modified.
SEQ ID NO: 6 of the ‘959 patent and instant SEQ ID NO: 6 are identical and instant claim 64 specifically recites position 341 is also modified; and also positions 333, 335, 336, 337, 338, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 352, 353, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 366, 370, 373, 374 may be modified.
As such, the claims of the ‘959 patent are taken as anticipatory over the instant claims.
Claims 41-45, 51, 64-73 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 12,371,685.
The claims of the ‘685 patent recite A modified PH20 polypeptide comprising an amino acid sequence, wherein: (a) at least 95% of the residues of the amino acid sequence of the modified PH20 polypeptide are identical to the residues in the amino acid sequence of SEQ ID NO: 35 when the sequence of the modified PH20 polypeptide is aligned at positions corresponding to the sequence set forth in the amino acid sequence of SEQ ID NO: 35 to maximize identical residues, and wherein terminal gaps are treated as non-identical; and (b) the amino acid sequence of the modified PH20 polypeptide comprises an amino acid modification at a position corresponding to position 324 with reference to amino acid positions set forth in the amino acid sequence of SEQ ID NO: 3; and (c) the modification at position 324 is a replacement selected from among D, N, and R, and wherein the modified PH20 polypeptide exhibits increased hyaluronidase activity compared to the hyaluronidase activity of the polypeptide set forth in the amino acid sequence of SEQ ID NO: 3, measured under identical conditions.
SEQ ID NO: 35/3 of the ‘685 patent differ from instant SEQ ID NO: 6 by removal of the first 35 amino acids (See sequence alignment above in 112(b) rejection). Thus, position 324 of SEQ ID NO: 35/3 corresponds to position 359 of SEQ ID NO: 6, which is currently claimed. In addition, according to both Table 3’s, replacing position 324 of SEQ ID NO: 3 with D, N or R results in a hyaluronidase having at least 40% activity, which is also currently claimed. As such, while the ‘ 685 patent is silent with regard to the hyaluronidase activity, it clear the substitutions with D, N or R will necessarily result in the claimed activity. As such, the claims of the ‘685 patent are taken as anticipatory of the instant claims.
Claims 41-45, 51, 64-73 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 12,104,185.
The claims of the ‘185 patent recite a method for increasing delivery of a therapeutic agent to a subject, comprising administering to a subject a pharmaceutical composition comprising: (a) a therapeutic agent; and (b) a modified PH20 polypeptide comprising an amino acid sequence, wherein: i. at least 95% of the residues of the amino acid sequence of the modified PH20 polypeptide are identical to the residues in an amino acid sequence selected from the group consisting of SEQ ID NOs: 3 and 32-66 when the sequence of the modified PH20 polypeptide is aligned at positions corresponding to the sequence selected from the group consisting of SEQ ID NOs: 3 and 32-66 to maximize identical residues; and ii. the amino acid sequence of the modified PH20 polypeptide comprises an amino acid modification at a position corresponding to position 320 with reference to amino acid positions set forth in SEQ ID NO: 3; and iii. the modification at position 320 is a replacement selected from the group consisting of H, K, R and S.
SEQ ID NO: 3 of the ‘185 patent differ from instant SEQ ID NO: 6 by removal of the first 35 amino acids (See sequence alignment above in 112(b) rejection). Thus, position 320 of SEQ ID NO: 3 corresponds to position 355 of SEQ ID NO: 6, which is currently claimed. In addition, according to both Table 3’s, replacing position 324 of SEQ ID NO: 3 with H, K, R or S results in a hyaluronidase having at least 40% activity, which is also currently claimed. As such, while the ‘185 patent is silent with regard to the hyaluronidase activity, it clear the substitutions with H, K, R or S will necessarily result in the claimed activity. As such, the claims of the ‘185 patent are taken as anticipatory of the instant claims.
Conclusion
No claim is allowed.
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/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656 15 July 2026
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