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
Claims 74-77, 79-114, filed 11/17/2025, are pending. Claims 74-77, 79-93, 95-103, and 105-114 are under examination. Claims 1-73 are cancelled. Claims 74-77 and 79-114 are new. Claim 78 is missing. Claims 94 and 104 cannot be examined because they depend on missing claim 78.
The numbering of claims is not in accordance with 37 CFR 1.126 which requires the original numbering of the claims to be preserved throughout the prosecution. When claims are canceled, the remaining claims must not be renumbered. When new claims are presented, they must be numbered consecutively beginning with the number next following the highest numbered claims previously presented (whether entered or not).
Claim 78 is missing. For purposes of examination and compact prosecution, the scope of claims 79-114 will be examined as if they were renumbered 78-113, respectively, and the claims will be referred to by these renumbered claim numbers hereafter. The parent claims to which each dependent claim refers to will also be examined as renumbered accordingly in the dependent claims, hereafter.
Priority
The instant application claims priority to provisional Application No. 63082888 (filed 09/24/2020). Provisional Application No. 63082888 discloses Tables 1-13, Figures 1-9, and Examples 1-3, which match the corresponding disclosures in the instant specification, which are directed towards enzyme activity within the formulations after storage at 5°C and 25°C, as is relevant to instant claims 74-75, 77-78, 80-81, 83-84, 86-87, 89-90, 92-93, 95-96, 98-100, 102-103, 105-106, 108-109, and 111-113. Provisional Application No. 63082888 does not disclose teachings of enzyme activity within the formulations after storage at 35°C, which is relevant to instant claims 76, 79, 82, 85, 88, 91, 94, 97, 101, 104, 107, and 110. Accordingly, the effective filing date of instant claims 74-75, 77-78, 80-81, 83-84, 86-87, 89-90, 92-93, 95-96, 98-100, 102-103, 105-106, 108-109, and 111-113 is 09/24/2020.
The instant application claims priority to PCT Application No. US21/51641 (filed 09/23/2021). PCT Application No. US21/51641 discloses Tables 1-17, Figures 1-18, and Examples 1-10, which match the corresponding disclosures in the instant specification, which are directed towards enzyme activity within the formulations after storage at 5°C, 25°C, and 35°C. Figures 16 and Example 9, which were not in provisional Application No. 63082888 are relevant to enzyme activity within the formulations after storage at 35°C, which is relevant to instant claims 76, 79, 82, 85, 88, 91, 94, 97, 101, 104, 107, 110. Accordingly, the effective filing dates of instant claims 76, 79, 82, 85, 88, 91, 94, 97, 101, 104, 107, and 110 is 09/23/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/05/2024 and 11/17/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The information disclosure statement filed 09/16/2024 fails to comply with 37 CFR 1.98(a)(1), which requires the following: (1) a list of all patents, publications, applications, or other information submitted for consideration by the Office; (2) U.S. patents and U.S. patent application publications listed in a section separately from citations of other documents; (3) the application number of the application in which the information disclosure statement is being submitted on each page of the list; (4) a column that provides a blank space next to each document to be considered, for the examiner’s initials; and (5) a heading that clearly indicates that the list is an information disclosure statement. Therefore, the foreign patent document submitted in the file wrapper that were not disclosed on the IDS has not been considered.
The information disclosure statement filed 04/04/2024 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered. Therefore, the foreign patent submitted in the IDS without a copy of the document has not been considered.
Sequence Compliance
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
The Incorporation by Reference statement in the Specification entered 03/23/2023 refers to a file name, 25106WOPCT-SEQLIST-21SEP2021.txt, that does not match the file name of the current working copy of the Sequence Listing, 25106WOPCTSEQLIST.txt. The file name of the sequence listing must match the file name of the sequencing listing reported in the Incorporation by Reference statement in the specification.
Claim Objections
Note: for the purposes of examination, the scope of the claims will be examined as if they were renumbered according to disclosure in the Claim Status section of this office action.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Applicant is advised that should claim 99 be found allowable, claim 111 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim 74-113 are objected to because of the following informalities:
There is an “or” missing between the concentration ranges of the PH20 variant fragment.
Claim 113 is objected to because of the following informalities:
The complete meaning of the abbreviation “MSI-H” is missing.
Appropriate correction is required.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
Because these claim limitations are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, they are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
Claims 74-113 are being interpreted under 35 U.S.C. 112(f).
Claim 74 and its dependent claims 77, 80, 83, 86, 89, 92, 95, 98, 99, 102, 105, 108, 111, 112, 113 are drawn to “means for retaining the enzymatic activity of the PH20 variant fragment after storage at 25°C for 3 months.” Claim 75 and its dependent claims 78, 81, 84, 87, 90, 93, 96, 100, 103, 106, 109 are drawn to “means for retaining the enzymatic activity of the PH20 variant fragment after storage at 5°C for 6 months or 3 months.” Claim 76 and its dependent claims 79, 82, 85, 88, 91, 94, 97, 101, 104, 107, 110 are drawn to “means for enhancing the enzymatic activity of the PH20 variant fragment compared to the formulation without pembrolizumab after storage at 35°C for 1 week.” The broadest reasonable interpretation of these limitations is any condition that enables the claimed function. The specification teaches that Figures 9, 12, and 15 and Tables 5, 15, and 17 disclose formulations where the enzymatic activity of the PH20 variant fragment is retained after storage at 25°C for 3 months. The specification teaches that Figures 8 and 11, and Tables 5 and 15 disclose formulations where the enzymatic activity of the PH20 variant fragment is retained after storage at 5°C for 6 months or 3 months. The specification teaches Figure 16 and Example 9 disclose formulations wherein the enzymatic activity of the PH20 variant fragment with pembrolizumab is enhanced compared to the formulation without pembrolizumab after storage at 35°C for 1 week.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 98 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 98 recites the formulation of claim 86, wherein the PH20 variant fragment is at about 1000 to about 6000 U/ml. However, the formulation of claim 86 already recites a formulation, wherein the PH20 variant fragment is at about 1000 to about 6000 U/ml. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 74-113 are indefinite and rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. The specification fails to adequately link or associate particular corresponding structures, materials, or acts to the functional limitation of the “means” recited in the claims.
The claims are directed to a formulation comprising of pembrolizumab and a PH20 variant fragment. The claims further recite “means for retaining the enzymatic activity of the PH20 variant fragment after storage at 25°C for 3 months”, “means for retaining the enzymatic activity of the PH20 variant fragment after storage at 5°C for 6 months or 3 months,” or “means for enhancing the enzymatic activity of the PH20 variant fragment compared to the formulation without pembrolizumab after storage at 35°C for 1 week”
The specification teaches formulations containing pembrolizumab, the PH20 variant fragment enzyme, histidine buffer, methionine, sucrose, and sometimes PS-80, all at various concentrations that are taught to exhibit the claimed function regarding enzyme activity.
However, the specification does not distinctly and specifically disclose which components in the formulation are necessary and sufficient to achieve the claimed function. Therefore, the structure related to the claimed function is unclear and the means to achieve this function is indefinite. Are all the components at all the concentrations disclosed in all the example formulations necessary in retaining or enhancing the PH20 variant fragment enzyme or is it only a subset of the components?
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 74-85 recite the broad recitation about 0.0009 mg/ml to about 0.050 mg/ml of a PH20 variant fragment, about 150 to about 5000 U/ml, about 1000 to about 6000 U/ml of a PH20 variant fragment. The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The term “retaining” in claims 74-75 and their dependent claims, 77-78, 80-81, 83-84, 86-87, 89-90, 92-93, 95-96, 98-100, 102-103, 105-106, 108-109, 111-113 is a relative term which renders the claim indefinite. The term “retaining” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The term “enhance” in claims 76 and its dependent claims, 79, 82, 85, 88, 91, 94, 97, 101, 104, 107, 110 is a relative term which renders the claim indefinite. The term “enhance” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
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.
Written Description
Lack of written description for structure for functional language
Claims 74-113 are rejected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, because the claim purports to invoke 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, but fails to recite a combination of elements as required by that statutory provision and thus cannot rely on the specification to provide the structure, material or acts to support the claimed function. As such, the claim recites a function that has no limits and covers every conceivable means for achieving the stated function, while the specification discloses at most only those means known to the inventor. Accordingly, the disclosure is not commensurate with the breadth of the claim.
The written description does not adequately link or associate particular structures, materials, or acts to the function recited in the functional language claim limitation. The written description does not teach what components in the formulations should be included in the scope of the means to achieve the claimed function. One skilled in the art would not inherently know what specific structures in the specification are necessary and sufficient to achieve the functional language claim limitation.
The claims are directed to a formulation that comprises of pembrolizumab and a PH20 variant fragment disclosed in SEQ ID NO: 23 and a means for retaining the enzymatic activity of the PH20 variant fragment after storage at 25°C for 3 months; or means for retaining the enzymatic activity of the PH20 variant fragment at 5°C for 6 months or 3 months; or means for enhancing the enzymatic activity of the PH20 variant fragment compared to the formulation without pembrolizumab after storage at 35°C for 1 week. The claims further recite concentration ranges and values for pembrolizumab and the PH20 variant.
Although the specification discloses formulations, consisting of methionine, sucrose, PS-80, histidine buffer, pembrolizumab, and a PH20 variant fragment enzyme, that are disclosed to have the claimed function regarding the enzymatic activity of the PH20 variant fragment enzyme at the claimed storage conditions, it fails to particularly point out and distinctly claim which components of the formulations are necessary and sufficient in achieving the disclosed functions (Figures 8-9, 11-12, and 14-16).
The state of the art regarding pharmaceutical formulations comprising hyaluronidase teaches that formulation development is done empirically to determine the long-term enzyme activity at each formulation condition (Guo et al., An industry perspective on hyaluronidase co-formulated biopharmaceutics. Journal of Controlled Release, 381 (2025), published 02/19/2025, hereafter referred to as Guo. See section 4.1 Stability and formulations of commercial hyaluronidase co-formulated products, page 4; and section 5.2 Formulation development, page 7-8). Therefore, formulation components and conditions needed to meet the claimed function regarding enzyme activity is unpredictable. One of ordinary skill in the art would not inherently know or be able to predict what components are needed to meet the claimed function regarding enzyme activity. Therefore, the scope of the corresponding structure is unknown.
Without sufficient disclosure on the corresponding structure linked to the function recited in the claims and associated functional language claim limitation, the claim is drawn to all means of retaining or enhancing the enzymatic activity as disclosed in the claims. The specification teaches some example formulations that meet the functional language claim limitation. However, the state of the art teaches that there are multiple options for each class of formulation excipients (Guo, section 5.2 Formulation development, page 7-8). Further, the eight clinically approved marketed pharmaceutical formulations containing a recombinant human PH20 hyaluronidase (rHuPH20) have formulations that all have different component combinations than disclosed in the instant application (Guo, Table 3, page 7). Therefore, the means to stabilize hyaluronidase activity in formulations is broad and cannot be sufficiently claimed by the few formulations disclosed in the instant specification that are identical to each other in component composition and vary only in concentrations. Therefore, the specification also does not disclose sufficient species to encompass the entire scope of the claims.
In conclusion, claims 74-113 lack written description for the scope of the structure corresponding to the claimed function and for the full breadth of the ranges and cancers claimed. The specification does not disclose all the formulation combinations claimed, and therefore, it is not possible to ascertain the enzyme activity of these claimed formulation. The specification further teaches that the results they did obtain were unexpected in retaining or enhancing the enzyme activity in the formulation, but without disclosure of the specific components implicated in these functions. The state of the art teaches that functions of polypeptides in formulations is unpredictable. The state of the art is silent on the prediction of PH20 variant fragment enzymatic activity in light of the unexpected results regarding its dependency on the concentration of pembrolizumab. Therefore, one skilled in the art cannot reasonably conclude that possession of some formulations with the claimed functions implies possession of formulations with different amounts of enzyme or pembrolizumab.
Lack of written description for full breadth of claimed ranges:
Additionally, claims 75-76, 78-79, 81-82, 84-85, 87-88, 90-91, 93-94, 96-97, 99-101, 103, 112-113 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim 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, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention.
For compact prosecution, the three ranges of the PH20 variant fragment enzyme recited in the instant claims are interpreted to be alternative options for the range of a PH20 variant fragment in the formulation.
Regarding claim 75 and its dependent claims 78, 81, 84, 87, 90, 93, 96, 100, and 103 the specification discloses that Figure 8 teaches retained enzyme activity compared to the initial time point, T0, after 3 months or 6 months at 5°C in formulations comprising of:
0.012 mg/ml of PH20 variant fragment 2 and 0, 100, 130, or 165 mg/ml of pembrolizumab; or
0.03 mg/ml PH20 variant fragment 2 and 0, 100, 130, or 165 mg/ml of pembrolizumab.
The specification further discloses that Figure 11 teaches retained enzyme activity compared to the initial time point, T0, after 3 and 6 months at 5°C, with or without stainless steel stress in formulations comprising of:
2000 U/ml of PH20 variant fragment 2 and 130 or 165 mg/ml of pembrolizumab.
Regarding claim 76 and its dependent claims 79, 82, 85, 88, 91, 94, 97, and 101, the specification discloses that Figure 16 teaches formulations comprising of pembrolizumab and the claimed PH20 variant fragment with enhanced enzyme activity compared to formulations without pembrolizumab after storage at 35°C for 1 week. The conditions contain [excipient conditions] and 2000 U/ml of PH20 variant fragment 2 and 5, 25, 50, 75, 100, 130, or 165 mg/ml of pembrolizumab.
Regarding claims 112-113, the specification discloses the method comprises administering an effective amount of any of the formulations of the instant invention to the subject, wherein in some embodiments of this method, the formulation is administered to the subject by subcutaneous administration (page 43, lines 5-9). The specification then lists embodiments of the target cancers (pages 43-48). The specification discloses the dose amount and dosing frequency of the formulation will depend on the particular therapeutic agent, the severity of the cancer being treated, and patient characteristic (page 49, lines 19-23) and provides references and examples of methods (pages 49-51).
Written description for claim 75 and its dependent claims 78, 81, 84, 87, 90, 93, 96, 100, and 103 is met for the ranges or values of pembrolizumab and the claimed PH20 variant fragment in formulations that were disclosed to retained enzymatic activity of the PH20 variant fragment after storage at the temperatures and time ranges claimed, as taught by Figures 8 and 11 stated above.
Written description for claim 76 and its dependent claims 79, 82, 85, 88, 91, 94, 97, and 101 is met for the ranges or values of pembrolizumab and the claimed PH20 variant fragment, in formulations that were disclosed to show enhanced enzymatic activity of the PH20 variant fragment compared to formulations without pembrolizumab, after storage at the temperatures and time ranges claimed, as taught by Figure 16, stated above.
Regarding claims 75, 78, and 87, the specification does not support the full claimed range of pembrolizumab and the full claimed range of the claimed PH20 variant fragment. The specification does not support the range of about 50 to up to but not including about 100 mg/ml of pembrolizumab. The specification does not support the range of about 75 to up to but not including about 100 mg/ml of pembrolizumab. The specification does not support the full claimed range besides 2000 U/ml and 5000 U/ml of the claimed PH20 variant fragment.
Regarding claims 81, 84, 90, 93, and 96, the specification does not support the full concentration range of the claimed PH20 variant fragment. . The specification does not support the full claimed range besides 2000 U/ml and 5000 U/ml of the claimed PH20 variant fragment.
Regarding claims 100 and 103, the specification does not support the range of about 75 to up to but not including about 100 mg/ml of pembrolizumab.
Regarding claims 76, 79, 82, 85, 88, 91, 94, 97, and 101, the specification does not support the full claimed range of the claimed PH20 variant fragment. The specification does not support the full claimed range besides 2000 U/ml of the claimed PH20 variant fragment.
Regarding claims 112 and 113, the specification does not teach treating all cancers and the specific cancers claimed with the formulation claimed. Possessing a formulation that has the claimed PH20 enzyme activity does not necessarily translate to possessing a method, using this formulation, that can treat cancer. There is no disclosure teaching the antibody activity. There is also no disclosure teaching any of the formulations in treating any cancer.
Regarding claims 75 and dependent claims 78, 81, 84, 87, 90, 93, 96, 100, and 103, the state of the art is silent on the dependency of the enzyme activity on the presence of pembrolizumab. Therefore, written description for the conditions claimed in the instant application must rely on the written specification of the instant application. Due to the unexpected results of the dependency of the enzyme activity on the pembrolizumab concentration, a person skilled in the art cannot reasonably extrapolate the enzyme activity outside of the explicitly taught pembrolizumab concentrations. It is further unclear what role the concentration of PH20 variant fragment plays in retaining the enzymatic activity in light of these unexpected results. Therefore, instant claims lack written description support for the entire pembrolizumab concentration and entire PH20 variant fragment concentration.
Regarding claims 76 and dependent claims 79, 82, 85, 88, 91, 94, 97, and 101, there is conflicting data disclosed in patent application Alteogen Inc. (US 20210363270 A1. Park, S., et al. Pharmaceutical composition for subcutaneous injection comprising human hyaluronidase PH20 variant and drug. Effectively filed 03/24/2020 from PCT filing benefit, hereafter referred to as Alteogen '270) for conditions under heat-stress. This application teaches a formulation referred to as Formulation 19 (Table 12; Figure 18), which shows decreased enzymatic activity, below 500 U/ml, after storage at 40°C for 7 days compared to day 0, which showed enzymatic activity between 1500 U/ml and 2000 U/ml (Example 26; page 26, paragraph 241). The application discloses the PH20 variant fragment in Formulation 19, as identified by SEQ ID NO: 44, which has 100% sequence match with SEQ ID NO: 23 of the instant application. Furthermore, the formulation is the same as that disclosed in instant application Figure 16 and instant Example 9 at the 25 mg/ml Pembrolizumab concentration condition. Both formulations in the reference application and the instant application comprise of pembrolizumab, the same claimed PH20 variant fragment, and the same excipients at the same concentrations. However, the instant specification teaches that this condition, after storage at 35°C for 1 week, had enzyme activity between 1500 U/ml and 2000 U/ml. Although the storage temperatures are different, 35°C in the instant versus 40°C in the reference application, the significant difference in activity between these disclosures for the same formulation speaks to the unpredictability of the enzyme activity with slight changes to the storage conditions.
Regarding claims 112-113, without disclosures on the treatment of cancer using the disclosed formulations, the state of the art teaches that pembrolizumab monotherapy or in combination therapy with chemotherapy or other immunotherapies has been shown to treat certain cancers. The art teaches pembrolizumab is FDA-approved or FDA-approved under accelerated approval as indicated for melanoma, non-small cell lung cancer, urothelial cancer, gastric cancer, gastroesophageal junction adenocarcinoma, hepatocellular cancer, merkel cell carcinoma, renal cell carcinoma, Hodgkin lymphoma, small cell lung cancer, cervical cancer, Tumor Mutational Burden High, and MSI-H cancer. Non-FDA approved indications in later-stage clinical trials include: breast cancer, cutaneous squamous cell carcinoma, mesothelioma, ovarian cancer, esophageal cancer, and colorectal cancer (Flynn et al., Pembrolizumab., published 06/26/2023. National Library of Medicine, StatPearls, PMID: 31536223, Bookshelf ID: NBK546616, hereafter referred to as Flynn.).
The drug label disclosure for Keytruda QLEX discloses pharmaceutical formulation comprising of pembrolizumab and berahyaluronidase alfa, which is a variant of human hyaluronidase PH20 with an undisclosed sequence (Merck Sharp & Dohme LLC, KEYTRUDA QLEX, published 09/2025, hereafter referred to as Merck). This disclosure teaches indications for these formulations, with and without other formulations, in treating melanoma, non-small cell lung cancer, head and neck cancer, urothelial cancer, breast cancer, gastric cancer, hepatocellular cancer, merkel cell carcinoma, renal cell carcinoma, endometrial carcinoma, cutaneous squamous cell carcinoma, mesothelioma, esophageal cancer, biliary tract cancer, colorectal cancer, cervical cancer, Tumor Mutational Burden High, and MSI-H cancer.
The state of the art teaches that combination therapy with hyaluronan-degrading enzyme and an immune checkpoint inhibitor could be used to treat cancers (Halozyme, Inc., US 11414489 B2, Rosengren et al., Combination Therapy with Hyaluronan-Degrading Enzyme and An Immune Checkpoint Inhibitor, Effective filing date: 08/28/2015; herein referred to as Halozyme). The enzymes disclosed do not match the sequence from instant SEQ ID NO: 23 but pembrolizumab is disclosed as one exemplary immune checkpoint inhibitor (Halozyme, Table 3). The state of the art teaches that recombinant human PH20 (rHuPH20), which is the PH20 fragment that the instantly claimed enzyme is a variant of, has been approved in the United States and/or global markets as a drug delivery technology for daratumumab, trastuzumab, pertuzumab, trastuzumab, rituximab, and immune globulin (Inoue, Y., Subcutaneous delivery of immune checkpoint inhibitors: new route replacing intravenous administration, Transl Lung Cancer Res. 13(4):947-951, published 04/18/2024, hereafter referred to as Inoue). The state of the art teaches that a PH20 variant fragment having the amino acid of SEQ ID NO: 99 in US12371683B2, which has 100% sequence match to instant SEQ ID NO: 23, would be the preferred variant in pharmaceutical compositions (Column 13, lines 47-50) wherein one exemplary composition could contain an immune checkpoint inhibitor (Column 19, lines 15-16) (Alteogen Inc., US12371683B2, Park et al., Hyaluronidase Variants And Pharmaceutical Composition Comprising the Same, effectively filed 07/25/2018, hereafter referred to as Alteogen ‘683).
These references teach the potential of using formulations comprising of a checkpoint inhibitor and a hyaluronidase in treating cancers, but there is yet explicit support for the exact combination of pembrolizumab and the claimed PH20 variant fragment in treating cancers. These references also teach indications for pembrolizumab and indications for Keytruda QLEX, which comprise of pembrolizumab and a PH20 variant, however, these indications do not encompass all cancers, as claimed in claim 112, and all the cancers claimed in claim 113.
Regarding claim 112, the state of the art taught by the National Institute of Health teaches that pembrolizumab is not indicated for all cancers. Pembrolizumab is not recommended, for example, for PMBCL (primary mediastinal large B-cell lymphoma) patients who require urgent cytoreductive therapy or for MSI-H central nervous system pediatric cancer (Flynn).
Regarding claim 113, there is insufficient data in the state of the art to determine whether the formulation as claimed can be used to treat all the cancers that were not explicitly indicated for pembrolizumab or Keytruda QLEX. This includes multiple myeloma, endometrial carcinoma, non-Hodgkin lymphoma, anal cancer, thyroid cancer, salivary cancer, and glioblastoma.
In conclusion, claims 75-76, 78-79, 81-82, 84-85, 87-88, 90-91, 93-94, 96-97, 99-101, 103, 112-113 lack written description for the full breadth of the claims. In conclusion, claims 112-113 lack written description for treating cancers unsupported by the written specification and the state of the art. The written specification and the state of the art does not support the claimed method that administering the claimed formulations will treat all cancers in claim 112 and all the claimed cancers in claim 113. The state of the art provides reasonable support for the method to treat some, but not all, of the cancers with the claimed formulation based on the indications of pembrolizumab co-formulated with a PH20 variant and the indications of pembrolizumab and the teachings that adding a PH20 variant has shown beneficial effects for pembrolizumab therapies.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is severable from its enablement provision.
Enablement
Claim 76 and dependent claims 79, 82, 85, 88, 91, 94, 97, 101, 104, 107, and 110 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not reasonably provide enablement for a means for enhancing the enzymatic activity of the PH20 variant fragment compared to the formulation without pembrolizumab after storage at 35°C for 1 week. 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 the invention commensurate in scope with these claims.
The specification is not enabling, as determined by the factors set forth in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1998).
Breadth of the claims: The claims recite means for enhancing enzyme activity for the PH20 variant fragment in formulations with pembrolizumab compared to formulations without pembrolizumab, after the formulations are stored at 35°C for 1 week. The claims recite ranges of PH20 variant fragment enzyme concentrations and ranges of pembrolizumab concentrations for which this enhancement of enzymatic activity is claimed. The application claims means to enhance the enzymatic activity, but does not explicitly teach which components in their disclosed formulations have a role in this claimed function.
Nature of the invention: The claims are drawn to pharmaceutical formulations for human patients that comprise a PH20 variant fragment enzyme and means for enhancing enzyme activity for the PH20 variant fragment in formulations with pembrolizumab compared to formulations without pembrolizumab, after these formulations are stored at 35°C for 1 week. The condition at 35°C is used to evaluate the stability of the PH20 variant fragment under thermal stress (Example 9, page 70, line 16-17). All other figures related to thermal stability of the enzymes were conducted at 5°C, 25°C, and 40°C instead of 35°C (Figures 2-6). The specification defines that for this instant application, 5°C is used interchangeably with 2°C-8°C (page 57, lines 26-27), which are commonly accepted temperatures for cold storage conditions. The nature of the invention can be understood to be directed towards conditions that maintain the enzyme activity at cold temperatures between 2°C-8°C; room temperatures, commonly referenced around 25°C; and heat stress. In light of the teachings at both 35°C and 40°C provided by the instant specification as a measure of thermal stability under heat stress, 35°C and 40°C are both understood to represent similar measures of heat stress.
The specification teaches that the dependency on pembrolizumab concentration in enhancing enzymatic activity is unexpected. The specification further teaches that the magnitude of the effect on enzyme activity is higher in formulations with higher pembrolizumab concentrations compared to formulations with lower pembrolizumab concentrations.
State of the prior art: The state of the art teaches that optimal formulation is essential to maintaining stability and enzymatic activity of the hyaluronidase (Guo, section 5.2. Formulation Development, paragraph 2). Guo teaches that development strategies for formulations with hyaluronidase enzymes, includes stable and active hyaluronidase enzyme selection; buffer selection; pH and ionic strength modulation; addition of viscosity-reducing agents; choosing compatible stabilizers, such as sugars, salts, amino acids, and surfactants; and considering lyophilization for proteins unstable in solution (section 5.2. Formulation development). Guo specifically teaches that antioxidants, such as methionine, plays a key role as a sacrificial agent against reactive oxygen species, undergoing oxidation itself to help deplete these oxidizing agents and help protect the hyaluronidase from oxidation. The art teaches that chelators may also help to protect the hyaluronidase from metal ions that may catalyze reactions that degrade hyaluronidase. The art teaches that hyaluronan (HA) hydrolysis catalyzed by hyaluronidase is strongly inhibited at low hyaluronidase to HA concentration ratios and low ionic strength conditions (Abstract, Lenormand et al, The hyaluronan–protein complexes at low ionic strength: How the hyaluronidase activity is controlled by the bovine serum albumin, Matrix Biology 28(2009) 365-372, published 07/28/2009, hereafter referred to as Lenormand). Therefore, the activity of a hyaluronidase enzyme has some dependency on the ratio of its concentration to its substrate’s concentration.
The art is silent on the role of pembrolizumab or other antibodies in stabilizing hyaluronidase and specifically, the PH20 variant.
Amount of direction provided by the inventor: This invention is drawn to a formulation that achieves a claimed function that is disclosed to be an unexpected result by the instant specification, wherein the function is enabled, at least in part, by the presence of pembrolizumab in the formulation. The specification still does not provide written support for the enzyme activity of all of all the claimed formulation conditions. The specification only discloses data on enzyme activity for 2000 U/ml PH20 variant fragment and 0, 5, 25, 50, 75, 100, 130, and 165 mg/ml pembrolizumab after 35°C for 1 week. In light of the unexpected result, it would not be reasonable for one of ordinary skill in the art to assume the enzyme activity at any formulation condition claimed that is not explicitly disclosed in the specification, by nature of being unable to assume results based on existing results when existing results are unexpected results. The specification does not teach information that would lead one of ordinary skill in the art to reasonably conclude that the results for 2000 U/ml would be the same for the entire claimed concentration range of the PH20 variant fragment. The amount of direction provided by the inventors is insufficient for the claimed limitation.
Level of predictability in the art: The art shows conflicting results with similar conditions and the state of the art is silent on the claimed function and the disclosed role of pembrolizumab on the function (Alteogen '270). Alteogen '270 teaches Figure 18, Formulation 19, which has the same formulation components and storage conditions set forth in instant Figure 16 at the 25 mg/ml pembrolizumab condition. The formulation contains 25 mg/ml pembrolizumab, 10 mM histidine, pH 5.5, 7% sucrose, 10 mM methionine, and 2000 U/ml of a hyaluronidase designated as HP46 of SEQ ID NO: 44, which has 100% sequence match to the instant SEQ ID NO: 23 (Table 12). The enzymatic activity is measured after storage for 7 days at 40°C. For this condition, Alteogen '270 teaches the enzymatic activity is below 500 U/ml and closer to 0 U/ml (Figure 18). However, for this same condition, the instant application teaches the enzymatic activity is around 1500 U/ml (instant Figure 16). The starting activity for enzymes in both Alteogen '270 and the instant application for this condition is between about 1500 U/ml to about 2000 U/ml. Therefore, Alteogen '270 teaches significantly less enzyme activity than the instant claims at the same conditions.
Furthermore, the eight existing marketed formulations containing a hyaluronidase and monoclonal antibody show a different composition, in terms of component and concentrations, for each formulation, with methionine being the only common component in all (Guo, Table 3 and section 4.1. Stability and formulations of commercial hyaluronidase co-formulated products). These formulations were optimized for hyaluronidase activity, as well as the antibody. Finally, antibody formulations are still determined empirically to directly see the results of the component combinations due to the unpredictable nature of protein and excipient interactions in solution. Therefore, in light of conflicting results in the art and teachings in the state of the art directed to the unpredictability of formulation components to stabilize enzyme activity, the level of predictability in the art is low regarding what conditions are optimal for hyaluronidase activity in coformulations with antibodies.
Level of one of ordinary skill: An ordinary artisan in the area of drug formulation development would have experience in screening components for particular activities. Screening for formulation combinations that retain the activity and functions of the formulation components at different storage conditions, while complex, is routine in the art. However, without sufficient written description by the instant disclosure, with the state of the art disclosing the unpredictable nature of bioactivity in pharmaceutical formulations and a broad scope of factors to consider, and with existing conflicting results in the art, the level of skill in the art needed to arrive at the claimed function would be high.
Existence of working examples: Examples are disclosed in the instant specifications for come claimed formulation conditions, but not all. However, conflicting enzyme activity results under the same formulation conditions between the instant application and the reference patent application raises the question of whether a person of ordinary skill in the art could replicate the results disclosed in instant Figure 16. Due to the dependency of hyaluronidase activity on the ratio of enzyme concentration to its substrate concentration, assay noise and differences in enzyme substrate could also be a factor in the results. Even if the results were different because of the difference in temperature between 35°C and 40°C, this speaks to the fragility and possibly transient nature of the invention around a narrow range of temperatures around physiological conditions. Therefore, even the disclosed examples are not enabled.
Quantity of experimentation needed to make or use the invention based on the content of the disclosure: It is unclear if the results that are disclosed could be replicated by one skilled in the art, in light of the conflicting results found in the art. Further, although it would be possible and reasonable for one skilled in the art to make the formulations that were not taught in the specifications, there is no indication found in the instant disclosure or the state of the art that these formulations would have the claimed function. There is no written description for the components that impact enhancing activity.
Without knowing what particular set of structures in the formulation, assays, and storage conditions are directly necessary and sufficient in enhancing the enzyme activity in the presence of pembrolizumab, the quantity of experimentation needed to replicate these findings expands to a limitless list of factors. The amount of experimentation would not be reasonable because it would require screening for formulations without guidance on the particular components to focus on and how to address issues with unpredictable results and conflicting results found in the prior art.
Further, even if the disclosed results were enabled, the specification only teaches the enzymatic activity results after storage for one week at 35°C for 2000 U/ml of PH20 variant fragment, and 0, 5, 25, 50, 75, 100, 130, and 165 mg/ml of pembrolizumab. Without written description support or support from the state of the art, the claims would lack the full scope of enablement for the conditions that are not explicitly taught in the specifications.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 74-75, 77-78, 80-81, 83-84, 86-87, 89-90, 92-93, 95-96, 98-100, 102-103, 105-106, 108-109, and 111 are rejected under 35 U.S.C. 103 as being unpatentable over Alteogen Inc. (US 20210363270 A1. Park, S., et al. Pharmaceutical composition for subcutaneous injection comprising human hyaluronidase PH20 variant and drug. Effectively filed 03/24/2020 from PCT filing benefit, hereafter referred to as Alteogen '270).
Regarding instant clams 74-75, 77-78, 80-81, 83-84, 86-87, 89-90, 92-93, 95-96, 98-100, 102-103, 105-106, 108-109, and 111 directed to a formulation comprising of pembrolizumab and a PH20 variant fragment, Alteogen '270 discloses a formulation comprising of pembrolizumab, 2000 U/ml hyaluronidase which has the amino acid sequence set forth in SEQ ID NO. 44, which has a 100% sequence match to instant SEQ ID NO: 23. The formulation further comprises of 10 mM histidine at pH 5.5, 7% sucrose, and 10 mM methionine. Formulation 21 further contains 0.02% polysorbate-80 (Table 12, page 26).
Alteogen '270 does not explicitly disclose in the same embodiment about 50 mg/mL to about 175 mg/mL of pembrolizumab in the formulation. Alteogen '270 also does not explicitly teach the enzymatic activity of the PH20 variant fragment after storage at 25°C for 3 months and after storage at 5°C for 6 months and 3 months.
However, Alteogen '270 also teaches that the content of the antibody drug in the pharmaceutical composition is most preferably 120 ± 18 mg/ml (paragraph 168), arriving at the same formulation composition disclosed in instant claims 74-75 and dependent claims. A formulation with the same antibody, same hyaluronidase, and same formulation composition as the instant application would be expected to have the hyaluronidase enzymatic activity profile as the instant disclosure, arriving at the functional limitation in the instant claims.
Therefore, it would have been prima facie obvious, before the effective filing date of the claimed invention, to a person of ordinary skill in the art, to improve the base formulation taught in formulation 21 in Alteogen ‘270 using the preferred antibody concentration taught by Alteogen '270 to arrive at the instantly claimed formulation.
Alteogen '270 teaches that hyaluronidases are added to antibody formulations meant for subcutaneous administration to reduce the side effects of this administration route and increase the delivery of the antibody into the body (paragraph 3). A person of ordinary skill in the art would understand the formulation containing a hyaluronidase is formulated for subcutaneous administration. Alteogen '270 teaches that subcutaneous injection volume is limited, and therefore, multiple doses or high concentration antibody doses are necessary (paragraph 3). Alteogen '270 further teaches that a clinically used subcutaneous injection formulation of trastuzumab contains 120 mg/ml of the antibody with 2000 U/ml of a hyaluronidase (paragraph 166) and that the content of the antibody drug in the pharmaceutical composition is most preferably 120 ± 18 mg/ml (paragraph 168).
A person of ordinary skill in the art would be motivated to increase the concentration of the pembrolizumab antibody in the base formulation from 25 mg/ml to help reduce the number of required administration doses for a subcutaneous injection, and would be motivated to increase it to a concentration, such as the preferred 120 mg/ml. A person of ordinary skill in the art would have a reasonable expectation that the antibody concentration increase would be tolerated in the formulation because the art teaches this concentration is a reasonable and desirable antibody concentration in clinical formulations. The intravenous formulation of pembrolizumab contains 25 mg/ml of antibody, which is the concentration in the base formulation taught by Alteogen '270. Although the clinical formulation for subcutaneous injection example provided in Paragraph 166 of Alteogen ‘270 is for a different antibody as the pembrolizumab instantly claimed, increasing the antibody concentration when reformulating a formulation from intravenous administration to subcutaneous administration is common and is routine optimization in the art.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that using a known technique to improve a known product ready for improvement to yield predictable results is obvious. In Alteogen '270, the base product is Formulation 21 which uses the lower concentration of antibody developed for intravenous injection but is being reformulated as a subcutaneous injection which has the disadvantage of a lower injection volume thereby necessitating a higher drug dose or more frequent dosing to compensate. The known technique for improving subcutaneous injection is increasing the concentration of the antibody, as taught by the preferred antibody concentration in Alteogen '270. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Claim 112-113 are rejected under 35 U.S.C. 103 as being unpatentable over Alteogen '270 as applied to claims 74-75, 77-78, 80-81, 83-84, 86-87, 89-90, 92-93, 95-96, 98-100, 102-103, 105-106, 108-109, and 111 above, and further in view of Rusquec et al (Rusquec, P., Clinical utility of pembrolizumab in the management of advanced solid tumors: an evidence-based review on the emerging new data. Cancer Management and Research, 4297-4312, Published 05/15/2019. Hereafter referred to as Rusquec).
Regarding instant claims 112-113 directed to a method of treating cancer using the claimed formulation, the teachings of Alteogen '270 directed to formulations are described above.
In regards to the method of using the formulations to treat diseases, Alteogen '270 further teaches that the effect of human PH20 variants can maximize the therapeutic effect of a drug used in combination with it (Abstract). Alteogen '270 further teaches a method of treating a disease using the formulations disclosed, wherein the disease that can be treated could be any disease that can be treated with the drug used in combination with the PH20 variant enzyme (paragraph 189). Specifically, the disease that can be treated may be cancer (paragraph 190).
Regarding claim 112-113, Alteogen '270 does not explicitly disclose which particular formulation can treat cancers and what particular cancers.
Rusquec teaches pembrolizumab is one of the most advanced immune checkpoint inhibitor antibodies for cancer care and has clinical utilities in managing advanced solid tumors (Page 4297, section Abstract). The indications for pembrolizumab include cancers, as recited in instant claim 112; specifically, melanoma, non-small cell lung cancer, squamous cell non-small cell lung cancer, bladder cancer, cervical cancer, gastric cancer, hepatocellular carcinoma, head and neck cancer, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors, which are included in the list of cancers in instant claim 113 (Pages 4299 and 4303, section 2. Approved indications for pembrolizumab).
Therefore, it would have been prima facie obvious, before the effective filing date of the claimed invention, to a person of ordinary skill in the art, to combine the method of using the formulation for treating a disease treatable by the antibody in the formulation taught by Alteogen '270 with the diseases that are treatable by pembrolizumab taught in Rusquec to arrive at the instantly claimed formulation. Although Alteogen '270 does not teach what the disclosed formulation can treat, according to the teaching that the disease treated could be any disease that can be treated with the drug used in combination with the PH20 variant enzyme, it would be obvious to one skilled in the art to understand that this teaches the treatable diseases to be ones that can be treated by the pembrolizumab in the formulation. One would be motivated to combine the drug formulation with the method to treat these cancers because these formulations are developed to maximize the therapeutic potential of the drug, in this case, pembrolizumab. The formulation is developed to enable subcutaneously-delivered, high-concentration pembrolizumab doses, which relieves hospital and patient burden over intravenous administration. Therefore, the combination of formulation optimization for disease treatment is common practice and desirable.
A person of ordinary skill in the art would be motivated to use the formulation to treat diseases based on the known indications of the antibody it contains because these diseases are most likely to be treated by the formulation.
A person of ordinary skill in the art would have a reasonable expectation of success and recognized that the results of the combination were predictable because PH20 hyaluronidases are widely applied in clinical use, including subcutaneous injection of an antibody therapeutic agent and works to increase the access of an anticancer therapeutic agent to the tumor cells by hydrolyzing hyaluronic acid in the extracellular matrix of tumor cells. Therefore, if pembrolizumab alone could help treat these diseases and coformulations of antibodies with PH20 hyaluronidase do not show adverse effects on the activity of either protein, it is reasonable to conclude that the formulation containing the PH20 hyaluronidase and pembrolizumab would allow the pembrolizumab to maintain its ability to treat the cancers it has already been indicated for, with routine optimization. The combination is thus also desirable to improve on the tumor access and penetration of formulations containing only pembrolizumab.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that combining prior art elements according to known methods to yield predictable results is obvious. Alteogen '270 teaches one element directed to a formulation containing pembrolizumab and a PH20 hyaluronidase used for cancer treatments. Alteogen '270 also teaches that this formulation can be used to treat diseases that pembrolizumab alone is used to treat. Rusquec teaches a second element directed to the specific cancers that can be treated by formulations containing pembrolizumab. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
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.
Application No. 17482650
Claims 74-111 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13, 15-35, 45-48, 52-55, and 58-70 of copending Application No. 17482650 (claims filed 11/17/2025, hereafter referred to as Application ‘650) in view of Alteogen Inc. (US 20210363270 A1. Park, S., et al. Pharmaceutical composition for subcutaneous injection comprising human hyaluronidase PH20 variant and drug. Effectively filed 03/24/2020 from PCT filing benefit, hereafter referred to as Alteogen, ‘270). Although the claims at issue are not identical, they are not patentably distinct from each other because they are directed to the same formulation embodiment.
Application ‘650 teaches a formulation comprising of an anti-human PD-1 antibody, a PH20 variant fragment, and sucrose; wherein the antibody has identical CDR sequences as pembrolizumab. SEQ ID NO: 1, 2, 3, 6, 7, and 8 are disclosed as the amino acid sequences for the CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3, respectively, of the antibody, which match with SEQ ID NO: 1,2, 3, 6,7, and 8 for the CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3, respectively, of pembrolizumab disclosed in the instant application (claim 1).
Claims 2-13 and 15-35 teach the concentration ranges of each component in the formulation, including histidine, methionine, the antibody, the PH20 variant fragment, and optionally, sucrose, as is relevant to instant claims 74-111.
Claims 45-48 further disclose the amino acid sequences for the variable heavy chain, variable light chain, heavy chain, and light chain of the antibody and teach the antibody is pembrolizumab or a variant of pembrolizumab, as is relevant to instant claims 74-111.
Claims 52-55 disclose the PH20 variant fragment sequence and disclose it as consisting of the amino acid sequence set forth in SEQ ID NO: 23, which has a 100% sequence identity match to the instant SEQ ID NO: 23, as is relevant to instant claims 74-111.
Claims 58-59 teach formulations comprising of components that match the instantly claimed formulation, and are at concentrations that either match or are within the instantly claimed range of claims 76 and its dependent claims 79, 82, 85, 88, 91, 94, 97, 101, 104, 107, and 110.
Claims 60-61 teach formulations comprising of components that match the instantly claimed formulation, and are at concentrations that either match or are within the instantly claimed range of claims 74-75 and their dependent claims 74-75, 77-78, 80-81, 83-84, 86-87, 89-90, 92-93, 95-96, 98-100, 102-103, 105-106, 108-109, and 111.
Claims 62-70 further limits previous formulations without specifically defined anti-human PD-1 antibody and PH20 variant fragment to the amino acid sequences that correspond to pembrolizumab and the instantly claimed PH20 variant fragment, as is relevant to instant claims 74-111.
Although not all claims of Application ‘650 explicitly teach the exact formulation of the instant claims, claims 58-61 teach the exact formulation as the instant claims. Application ‘650 does not explicitly teach the hyaluronidase enzyme activity after the formula has been stored according to the instant claims. However, a formulation with the same antibody, same hyaluronidase, and same formulation composition as the instant application would be expected to have the hyaluronidase enzymatic activity profile as the instant disclosure, arriving at the functional limitation in the instant claims.
Application ‘650 claims disclose the same formulation disclosed in the instant claims or it would have been obvious for a person of ordinary skill in the art to arrive at the instant claim formulations from Application ‘650 claims, in light of application claims 58-61 and teachings from the art. Therefore, it would have been prima facie obvious, to a person of ordinary skill in the art, that the formulation would also have the same enzymatic activity as the claimed formulation.
Alteogen ‘270 teaches that a formulation like the formulations claimed in Application ‘650 claims 58-61 is suitable for subcutaneous administration of the antibody contained in the formulation, thereby enabling treatment of diseases that the antibody is indicated for treatment (Table 12, page 26, formulas 19 and 21; Paragraph 3 and 168).
Therefore, it would have been prima facie obvious, to a person of ordinary skill in the art, to improve the base formulations taught in Application ‘650 claims and select the formulations disclosed in claims 58-61, motivated by the teachings of Alteogen ‘270 to arrive at the instantly claimed formulation.
A person of ordinary skill in the art would be motivated to use the specific formulation disclosed in claims 58-61 to improve on the base formulations of other claims in the application to develop a clinically useful formulation. This improvement towards clinical utility is also desirable. A person of ordinary skill in the art would have a reasonable expectation that the formulation would be successful because it matches with formulations taught in the art for subcutaneous injection of co-formulated pembrolizumab and the instantly claimed hyaluronidase.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that using a known technique to improve a known product ready for improvement to yield predictable results is obvious. The base product are the generic formulas claimed in Application ‘650. The known techniques for improving the formulations are the teachings of Alteogen ‘270 that motivate the use of the specific formulations taught in Application ‘650. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Claims 112-113 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13, 15-35, 45-48, 52-55, and 58-70 of copending Application No. 17482650 in view of Alteogen ‘270 as applied to claims 74-111 above, and further in view of Rusquec et al (Rusquec, P., Clinical utility of pembrolizumab in the management of advanced solid tumors: an evidence-based review on the emerging new data. Cancer Management and Research, 4297-4312, Published 05/15/2019. Hereafter referred to as Rusquec). Although the claims at issue are not identical, they are not patentably distinct from each other because they are directed to the same formulation embodiment.
The teachings of claims 1-13, 15-35, 45-48, 52-55, and 58-70 of copending Application No. 17482650 in view of Alteogen ‘270 as applied to claims 74-111 directed to the formulation are as above, and is also relevant to instant claims 112-113.
In regards to instant claims 112-113, which is further directed to the method of using the disclosed formulations to treat diseases, Alteogen ‘270 further teaches that the effect of human PH20 variants can maximize the therapeutic effect of a drug used in combination with it (Abstract). Alteogen ‘270 further teaches a method of treating a disease using the formulations disclosed, wherein the disease that can be treated could be any disease that can be treated with the drug used in combination with the PH20 variant enzyme (paragraph 189). Specifically, the disease that can be treated may be cancer (paragraph 190).
Regarding instant claims 112-113, Application ‘650 does not explicitly teach a method for treating cancers using the disclosed formulation. Alteogen ‘270 does not explicitly disclose which particular formulation can treat cancers and what particular cancers.
Rusquec teaches the cancers that could be treated by the disclosed formulations containing pembrolizumab. The indications for pembrolizumab include specific cancers, as recited in instant claim 112-113, wherein the specific cancers are disclosed in Rusquec (Pages 4299 and 4303, section 2. Approved indications for pembrolizumab).
Therefore, it would have been prima facie obvious, before the effective filing date of the claimed invention, to a person of ordinary skill in the art, to combine the method of using the formulation for treating a disease treatable by the antibody in the formulation taught by Alteogen ‘270 with the diseases that are treatable by pembrolizumab taught in Rusquec to arrive at the instantly claimed formulation. Although Alteogen ‘270 does not teach what the disclosed formulation can treat, according to the teaching that the disease treated could be any disease that can be treated with the drug used in combination with the PH20 variant enzyme, it would be obvious to one skilled in the art to understand that this teaches the diseases that can be treated by pembrolizumab in the formulation. One would be motivated to combine the drug formulation with the method to treat these cancers because these formulations are developed to maximize the therapeutic potential of the drug, in this case, pembrolizumab. The formulation is developed to enable subcutaneously-delivered, high-concentration pembrolizumab doses, which relieves hospital and patient burden over intravenous administration. Therefore, the combination of formulation optimization for disease treatment is common practice and desirable.
A person of ordinary skill in the art would be motivated to use the formulation to treat diseases based on the known indications of the antibody it contains because these diseases are most likely to be treated by the formulation.
A person of ordinary skill in the art would have a reasonable expectation of success and recognized that the results of the combination were predictable because PH20 hyaluronidases are widely applied in clinical use, including subcutaneous injection of an antibody therapeutic agent and works to increase the access of an anticancer therapeutic agent to the tumor cells by hydrolyzing hyaluronic acid in the extracellular matrix of tumor cells.
Therefore, if pembrolizumab alone could help treat these diseases and coformulations of antibodies with PH20 hyaluronidase do not show adverse effects on the activity of either protein, it is reasonable to conclude that the formulation containing the PH20 hyaluronidase and pembrolizumab would allow the pembrolizumab to maintain its ability to treat the cancers it has already been indicated for, with routine optimization. The combination is thus also desirable to improve on the tumor access and penetration of formulations containing only pembrolizumab.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that combining prior art elements according to known methods to yield predictable results is obvious. Application ‘650 and Alteogen ‘270 teaches one element directed to a formulation containing pembrolizumab and a PH20 hyaluronidase used for cancer treatments. teaches one element directed to a formulation containing pembrolizumab and a PH20 hyaluronidase used for cancer treatments. Alteogen ‘270 also teaches that this formulation can be used to treat diseases that pembrolizumab alone is used to treat. Rusquec teaches a second element directed to the specific cancers that can be treated by formulations containing pembrolizumab. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not been patented.
Application No. 18998765
Claims 74-111 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 9-12, 27-28, 42-45, 53, 63-80 of copending Application No. 18998765 (claims filed 01/27/2025, hereafter referred to as Application ‘765) in view of Alteogen Inc. (US 20210363270 A1. Park, S., et al. Pharmaceutical composition for subcutaneous injection comprising human hyaluronidase PH20 variant and drug. Effectively filed 03/24/2020 from PCT filing benefit, hereafter referred to as Alteogen ‘270). Although the claims at issue are not identical, they are not patentably distinct from each other because they are directed to the same formulation embodiment.
Claim 1 teaches a formulation comprising of an anti-human PD-1 antibody and a recombinant human PH20 variant or fragment; wherein the antibody has identical CDR sequences as pembrolizumab. SEQ ID NO: 1, 2, 3, 6, 7, and 8 are disclosed as the amino acid sequences for the CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3, respectively, of the antibody, which match with SEQ ID NO: 1,2, 3, 6,7, and 8 for the CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3, respectively, of pembrolizumab disclosed in the instant application, as is relevant to instant claims 74-111.
Claims 2-3, 9-12, further disclose the amino acid sequences for the variable heavy chain, variable light chain, heavy chain, and light chain of the antibody and acceptable variations, as is relevant to instant claims 74-111.
Claims 27-28 and 42-45, 63-64 further limits previous formulations without specifically defined excipient components and concentrations to include a histidine buffer, limitations on the pH of the buffer, sucrose, methionine, and optionally polysorbate 80, as is relevant to instant claims 74-111.
Claim 53 disclose the recombinant human PH20 sequence as consisting of the amino acid sequence set forth in SEQ ID NO: 18, which has a 100% sequence identity match to the instant SEQ ID NO: 23, as is relevant to instant claims 74-111.
Claims 65 teach formulations comprising of components that match the instantly claimed formulation, and are at concentrations that either match or are within the claimed range of claims 76 and its dependent claims 79, 82, 85, 88, 91, 94, 97, 101, 104, 107, and 110.
Claims 66 teach formulations comprising of components that match the instantly claimed formulation, and are at concentrations that either match or are within the claimed range of claims 74-75 and their dependent claims 74-75, 77-78, 80-81, 83-84, 86-87, 89-90, 92-93, 95-96, 98-100, 102-103, 105-106, 108-109, and 111.
Claims 67-80 disclose formulations comprising of components that match and further limit the range of antibodies and excipients to within the instant claims, as is relevant to instant claims 74-111.
Alteogen ‘270 teaches that a formulation like the formulations claimed in Application ‘765 claims 65-66 is suitable for subcutaneous administration of the antibody contained in the formulation, thereby enabling treatment of diseases that the antibody is indicated for treatment (Table 12, page 26, formulas 19 and 21; Paragraph 3 and 168).
Therefore, it would have been prima facie obvious, to a person of ordinary skill in the art, to improve the base formulations taught in Application ‘765 claims and select the formulations disclosed in claims 66-65, motivated by the teachings of Alteogen ‘270 to arrive at the instantly claimed formulation.
A person of ordinary skill in the art would be motivated to use the specific formulation disclosed in claims 66-65 to improve on the base formulations of other claims in the application to develop a clinically useful formulation. This improvement is also desirable. A person of ordinary skill in the art would have a reasonable expectation that the formulation would be successful because it matches with formulations taught in the art for subcutaneous injection of co-formulated pembrolizumab and the instantly claimed hyaluronidase.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that using a known technique to improve a known product ready for improvement to yield predictable results is obvious. The base product are the generic formulas claimed in Application ‘650. The known techniques for improving the formulations are the teachings of Alteogen ‘270 that motivate the use of the specific formulations taught in Application ‘650. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Claims 112-113 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 9-12, 27-28, 42-45, 53, 63-80 of copending Application No. 18998765 in view of Alteogen ‘270 as applied to claims 74-111 above, and further in view of claim 83 of copending Application No. 18998765, and further in view of Rusquec et al (Rusquec, P., Clinical utility of pembrolizumab in the management of advanced solid tumors: an evidence-based review on the emerging new data. Cancer Management and Research, 4297-4312, Published 05/15/2019. Hereafter referred to as Rusquec). Although the claims at issue are not identical, they are not patentably distinct from each other because they are directed to the same formulation embodiment.
The teachings of claims 1-3, 9-12, 27-28, 42-45, 53, 63-80 of copending Application No. 18998765 in view of Alteogen ‘270 as applied to claims 74-111 are as above, and is also relevant to instant claims 112-113.
Claim 83 further teaches a method for treating cancers in a human patient in need thereof, the method comprising administering an effective dose of the pharmaceutical composition disclosed, as is relevant to instant claims 112-113.
Application ‘765 and Alteogen ‘270 does not explicitly disclose which particular formulation can treat cancers and what particular cancers.
Rusquec teaches the cancers that could be treated by the disclosed formulations containing pembrolizumab. The indications for pembrolizumab include specific cancers, as recited in instant claim 112-113, wherein the specific cancers are disclosed in Rusquec (Pages 4299 and 4303, section 2. Approved indications for pembrolizumab).
Therefore, it would have been prima facie obvious, before the effective filing date of the claimed invention, to a person of ordinary skill in the art, to combine the method of using the formulation for treating a disease treatable by the antibody in the formulation taught by Alteogen ‘270 with the diseases that are treatable by pembrolizumab taught in Rusquec to arrive at the instantly claimed formulation. Although Application ‘765 and Alteogen ‘270 does not teach what the disclosed formulation can treat, according to the teaching that the disease treated could be any disease that can be treated with the drug used in combination with the PH20 variant enzyme, it would be obvious to one skilled in the art to understand that this teaches the diseases that can be treated by pembrolizumab in the formulation. One would be motivated to combine the drug formulation with the method to treat these cancers because these formulations are developed to maximize the therapeutic potential of the drug, in this case, pembrolizumab. The formulation is developed to enable subcutaneously-delivered, high-concentration pembrolizumab doses, which relieves hospital and patient burden over intravenous administration. Therefore, the combination of formulation optimization for disease treatment is common practice and desirable.
A person of ordinary skill in the art would be motivated to use the formulation to treat diseases based on the known indications of the antibody it contains because these diseases are most likely to be treated by the formulation.
A person of ordinary skill in the art would have a reasonable expectation of success and recognized that the results of the combination were predictable because PH20 hyaluronidases are widely applied in clinical use, including subcutaneous injection of an antibody therapeutic agent and works to increase the access of an anticancer therapeutic agent to the tumor cells by hydrolyzing hyaluronic acid in the extracellular matrix of tumor cells.
Therefore, if pembrolizumab alone could help treat these diseases and coformulations of antibodies with PH20 hyaluronidase do not show adverse effects on the activity of either protein, it is reasonable to conclude that the formulation containing the PH20 hyaluronidase and pembrolizumab would allow the pembrolizumab to maintain its ability to treat the cancers it has already been indicated for, with routine optimization. The combination is thus also desirable to improve on the tumor access and penetration of formulations containing only pembrolizumab.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that combining prior art elements according to known methods to yield predictable results is obvious. Application ‘765 and Alteogen ‘270 teaches one element directed to a formulation containing pembrolizumab and a PH20 hyaluronidase used for cancer treatments. Alteogen ‘270 also teaches that this formulation can be used to treat diseases that pembrolizumab alone is used to treat. Rusquec teaches a second element directed to the specific cancers that can be treated by formulations containing pembrolizumab. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not been patented.
Application No. 18998788
Claims 74-111 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 9-10, 12, 27-60 of copending Application No. 18998788 (claims filed 01/27/2025, hereafter referred to as Application ‘788) in view of Alteogen Inc. (US 20210363270 A1. Park, S., et al. Pharmaceutical composition for subcutaneous injection comprising human hyaluronidase PH20 variant and drug. Effectively filed 03/24/2020 from PCT filing benefit, hereafter referred to as Alteogen ‘270). Although the claims at issue are not identical, they are not patentably distinct from each other because they are directed to the same formulation embodiment.
Claims 1, 9-10, 12 teach a formulation comprising of an anti-human PD-1 antibody and a PH20 variant or fragment; wherein the antibody has identical CDR sequences as pembrolizumab. SEQ ID NO: 1, 2, 3, 6, 7, and 8 are disclosed as the amino acid sequences for the CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3, respectively, of the antibody, which match with SEQ ID NO: 1,2, 3, 6,7, and 8 for the CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3, respectively, of pembrolizumab disclosed in the instant application, as is relevant to instant claims 74-111.
Claims 2-4 further disclose the amino acid sequences for the variable heavy chain, variable light chain, heavy chain, and light chain of the antibody, as is relevant to instant claims 74-111.
Claims 27-44 further limits previous formulations without specifically defined excipient components and concentrations to include a histidine buffer, limitations on the pH of the buffer, sucrose, methionine, and optionally polysorbate 80 and provide concentration ranges or values, as is relevant to instant claims 74-111.
Claim 45 teaches formulations comprising of components that match the instantly claimed formulation, and are at concentrations that either match or are within the claimed range of claims 76 and its dependent claims 79, 82, 85, 88, 91, 94, 97, 101, 104, 107, and 110.
Claim 46 teaches formulations comprising of components that match the instantly claimed formulation, and are at concentrations that either match or are within the claimed range of claims 74-75 and their dependent claims 74-75, 77-78, 80-81, 83-84, 86-87, 89-90, 92-93, 95-96, 98-100, 102-103, 105-106, 108-109, and 111.
Claims 47-59 further limit the range of antibody concentration to within the instant claims, as is relevant to instant claims 74-111.
Claim 60 disclose the recombinant human PH20 sequence as consisting of the amino acid sequence set forth in SEQ ID NO: 18, which has a 100% sequence identity match to the instant SEQ ID NO: 23, as is relevant to instant claims 74-111.
Alteogen ‘270 teaches that a formulation like the formulations claimed in Application ‘765 claims 65-66 is suitable for subcutaneous administration of the antibody contained in the formulation, thereby enabling treatment of diseases that the antibody is indicated for treatment (Table 12, page 26, formulas 19 and 21; Paragraph 3 and 168).
Therefore, it would have been prima facie obvious, to a person of ordinary skill in the art, to improve the base formulations taught in Application ‘788 claims and select the formulations disclosed in claims 66-65, motivated by the teachings of Alteogen ‘270 to arrive at the instantly claimed formulation.
A person of ordinary skill in the art would be motivated to use the specific formulation disclosed in claims 45-60 to improve on the base formulations of other claims in the application to develop a clinically useful formulation. This improvement is also desirable. A person of ordinary skill in the art would have a reasonable expectation that the formulation would be successful because it matches with formulations taught in the art for subcutaneous injection of co-formulated pembrolizumab and the instantly claimed hyaluronidase.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that using a known technique to improve a known product ready for improvement to yield predictable results is obvious. The base product are the generic formulas claimed in Application ‘650. The known techniques for improving the formulations are the teachings of Alteogen ‘270 that motivate the use of the specific formulations taught in Application ‘650. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Claims 112-113 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 9-10, 12, 27-60 of copending Application No. 18998788 in view of Alteogen ‘270 as applied to claims 74-111 above, and further in view of Rusquec et al (Rusquec, P., Clinical utility of pembrolizumab in the management of advanced solid tumors: an evidence-based review on the emerging new data. Cancer Management and Research, 4297-4312, Published 05/15/2019. Hereafter referred to as Rusquec). Although the claims at issue are not identical, they are not patentably distinct from each other because they are directed to the same formulation embodiment.
The teachings of claims 1-4, 9-10, 12, 27-60 of copending Application No. 18998788 in view of Alteogen ‘270 as applied to claims 74-111 are as above, and is also relevant to instant claims 112-113.
Regarding instant claims 112-113, Application ‘765 and Alteogen ‘270 does not explicitly disclose which particular formulation can treat cancers and what particular cancers.
Rusquec teaches the cancers that could be treated by the disclosed formulations containing pembrolizumab. The indications for pembrolizumab include specific cancers, as recited in instant claim 112-113, wherein the specific cancers are disclosed in Rusquec (Pages 4299 and 4303, section 2. Approved indications for pembrolizumab).
Therefore, it would have been prima facie obvious, before the effective filing date of the claimed invention, to a person of ordinary skill in the art, to combine the method of using the formulation for treating a disease treatable by the antibody in the formulation taught by Alteogen ‘270 with the diseases that are treatable by pembrolizumab taught in Rusquec to arrive at the instantly claimed formulation. Although Application ‘788 and Alteogen ‘270 does not teach what the disclosed formulation can treat, according to the teaching that the disease treated could be any disease that can be treated with the drug used in combination with the PH20 variant enzyme, it would be obvious to one skilled in the art to understand that this teaches the diseases that can be treated by pembrolizumab in the formulation. One would be motivated to combine the drug formulation with the method to treat these cancers because these formulations are developed to maximize the therapeutic potential of the drug, in this case, pembrolizumab. The formulation is developed to enable subcutaneously-delivered, high-concentration pembrolizumab doses, which relieves hospital and patient burden over intravenous administration. Therefore, the combination of formulation optimization for disease treatment is common practice and desirable.
A person of ordinary skill in the art would be motivated to use the formulation to treat diseases based on the known indications of the antibody it contains because these diseases are most likely to be treated by the formulation.
A person of ordinary skill in the art would have a reasonable expectation of success and recognized that the results of the combination were predictable because PH20 hyaluronidases are widely applied in clinical use, including subcutaneous injection of an antibody therapeutic agent and works to increase the access of an anticancer therapeutic agent to the tumor cells by hydrolyzing hyaluronic acid in the extracellular matrix of tumor cells.
Therefore, if pembrolizumab alone could help treat these diseases and coformulations of antibodies with PH20 hyaluronidase do not show adverse effects on the activity of either protein, it is reasonable to conclude that the formulation containing the PH20 hyaluronidase and pembrolizumab would allow the pembrolizumab to maintain its ability to treat the cancers it has already been indicated for, with routine optimization. The combination is thus also desirable to improve on the tumor access and penetration of formulations containing only pembrolizumab.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that combining prior art elements according to known methods to yield predictable results is obvious. Application ‘788 and Alteogen ‘270 teaches one element directed to a formulation containing pembrolizumab and a PH20 hyaluronidase used for cancer treatments. Alteogen ‘270 also teaches that this formulation can be used to treat diseases that pembrolizumab alone is used to treat. Rusquec teaches a second element directed to the specific cancers that can be treated by formulations containing pembrolizumab. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not been patented.
Inventorship
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Conclusion
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/B.C./Examiner, Art Unit 1645
December 23, 2025
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674