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 .
Election/Restrictions
Applicant's election with traverse of
the PGRN-FBAC granulin domain of the PGRN protein, corresponding to SEQ ID NO: 2; and
a vector comprising a polynucleotide of SEQ ID NO: 7 encoding the PGRN-FBAC granulin domain of SEQ ID NO: 2
in the reply filed on 7/6/26 is acknowledged. The traversal is on the ground(s) set forth on pages 2-7 of the 7/26/26 Remarks, many of which pertain to restriction of inventions, which is not at issue given the instant requirement regarding species. This is not found persuasive because as to whether restriction is proper regarding species, the examiner encourages applicant and applicant attorney to consider the breadth of instant claim 1, in which the administered components include any active fragment of PGRN, this encompassing without any structure-limiting limitation (such as a specified core sequence) a potentially very large genus of peptides for which there is no indication of similarity of necessary core sequences, and a vector comprising a polynucleotide encoding such any active fragment of PGRN. The prior art cited in the 5/5/26 Restriction Requirement teaches that such combination was not a special technical feature, which applicant does not dispute. Why on page 7 of the 7/26/26 Remarks MPEP 806.03’s citation regarding claims defining “the same essential characteristics of a single disclosed embodiment” is raised as an argument is puzzling and unpersuasive given the possible breadth of the “active fragments of PGRN,” which have not been identified to be a “single disclosed embodiment”. The applicant appears to speculate that the examiner has not considered the claims without considering these “as a whole” and “interpreted in light of the description and drawings”, and this also is unpersuasive, lacking evidence and making no argument about how the claims should be interpreted alternatively to how the examiner interpreted them.
The requirement is still deemed proper and is therefore made FINAL.
The elected species were found free of the art and the examination extended for the benefit of compact prosecution.
Claim Status
Claims 1-8, 12 and 13 are pending and under examination.
Claims 1-8, 12 and 13 are rejected.
Priority
The instant application, filed 05/25/2023 is a National Stage entry of PCT/KR2021/017507 , International Filing Date: 11/25/2021
claims foreign priority to 10-2020-0161571, filed 11/26/2020
claims foreign priority to 10-2021-0160888, filed 11/22/2021.
Information Disclosure Statement
The Examiner has considered the reference(s) provided in the 5/25/23 and 3/20/25 Information Disclosure Statements, and provides a signed and dated copy of each herewith.
Drawings
The drawings are objected to because Figures 10-14 provide amino acid or nucleotide sequences that meet the sequence listing requirements but are not provided SEQ ID Numbers in the drawings or in the Brief Description of Drawings. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 112
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.
Claims 1-8, 12, 13 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(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated:
“To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the invention, with all its claimed limitations, not that which makes it obvious,” and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP § 2163. While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
Further, to provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include: a) the scope of the invention; b) actual reduction to practice; c) disclosure of drawings or structural chemical formulas; d) relevant identifying characteristics including complete structure, partial structure, physical and/or chemical properties, and structure/function correlation; e) method of making the claimed compounds; f) level of skill and knowledge in the art; and g) predictability in the art.
(1) Scope of the invention/Partial structure:
The claimed “pharmaceutically effective amount of a pharmaceutical composition” of claim 1 that is administered in its method of treating a pulmonary or airway fibrosis disease that comprises both “a progranulin (PGRN) protein or an active fragment thereof as an active ingredient; and a vector comprising a polynucleotide encoding the progranulin (PGRN) protein or an active fragment thereof as an active ingredient thereof, or a cell comprising the vector” encompasses a large and potentially diverse genus of proteins, peptides and polynucleotides in vectors or cells, with the active fragments, at least, having some activity. The subgenus of PGRN proteins does not explicitly require activity, however it is implied that these must have some beneficial effect to treat a pulmonary or airway fibrosis disease at least given the limitation that they be administered in a “pharmaceutically effective amount.” No specific sequence or structural requirements, such as a core sequence, or core sequences, is/are required in claim 1.
(2) Level of skill and knowledge in the art/predictability in the art:
The level of skill in the art is high, however the predictability in the relevant art, as to PGRN and its degradation products – granulins, is not high such that there is a high level of unpredictability with regard to the pro- vs. anti-inflammatory activities of the genus of fragments that could be included in the claims.
Wang et al., Protein Cell 2015, 6(11):792–803, teaches that PGRN is a 593-amino-acid autocrine growth factor that contains seven-and-a-half repeats of a cysteine-rich motif (CX5-6CX5CCX8CCX6CC XDX2HCCPX4CX5-6C) in the order P-G-F-B-A-C-D-E where A-G are full repeats and P is a half-motif, and inter alia that PGRN blocks the TNF-α induced respiratory burst in neutrophils (and has other anti-inflammatory effects), in contrast to granulin degradation products of PGRN, such that, for example, “The balance between anti-inflammatory PGRN and pro-inflammatory degraded granulin units is also important in neuroinflammation,” page 792. Wang extensively analyzes contradictory results in the field regarding progranulin/TNFR interactions, and on pages 798-799 teaches that “The importance and validity of PGRN-TNFR interactions in inflammatory diseases and conditions are supported by more recent experimental and epidemiological evidences. In addition to musculoskeletal disorders, including inflammatory arthritis (Tang et al., 2011; Tian et al., 2014b), osteoarthritis (Zhao et al., 2014) and bone healing (Zhao et al., 2013a), PGRN was also reported to play an important role in other common inflammatory diseases (Table 1).”
Wang also teaches the following, “The domains of PGRN required for binding to TNFR were then determined through a series of PGRN deletion mutants and three fragments composed of granulin F, A, C and their adjacent linkers were found to be responsible for the binding to TNFR. These three fragments most likely mimic the trimer structure of TNF when binding to TNFR (Wu and Siegel, 2011). Based on these results, Tang et al. further generated an engineered molecule called Atsttrin that only contained half Grn F, A, C, and was found to still bind to TNFR. Atsttrin was shown to have even better therapeutic effects than PGRN in treating inflammatory arthritis (Tang et al., 2011). In brief, this unexpected discovery of PGRN-TNFR interaction provided the molecular insights into the mechanism underlying PGRN mediated anti-inflammatory activities and might present PGRN and its engineered derivative, Atsttrin, as the next generation drug target for various kinds of inflammatory diseases (Liu, 2011; Liu and Bosch, 2012; Sfikakis and Tsokos, 2011; Wu and Siegel, 2011).”
The binding of Atsttrin to TNFR was studied also in Liu et al., PLOS ONE, March 2014 | Volume 9 | Issue 3 | e92743, 8 pages, this however focusing on the therapeutic action in inflammatory arthritis for this specific active derivative of PGRN.
Also, WO 2012/122464 A1, published 9/13/12 (Liu), provided in 3/20/25 IDS so copy not provided, teaches and evaluates a known shortened form of human progranulin (PRGN) identified as Atsttrinα, corresponding to SEQ ID NO:2 in Liu, and three variants of this protein designated by α(plus a number), see paras 76-77, those variants corresponding to SEQ ID Numbers 3-5. These do not include the “B” motif.
(3) Relevant identifying characteristics including complete structure, partial structure, physical and/or chemical properties, and structure/function correlation:
The instant specification teaches and evaluates full length PRGN and specific-sequence fragments it identifies as FBAC, BACD, and CDE, and also claims C by itself.
Other than teaching and evaluating the three specific-sequence fragments, FBAC corresponding to SEQ ID NO:2 with 333 amino acids, BACD corresponding to SEQ ID NO:3 with 305 amino acids, and CDE corresponding to SEQ ID NO:4 with 242 amino acids, there are no substantive detailed disclosures of what subsequence, linkers, or portions must be retained in “active” fragments, nor what must be avoided in fragments to avoid anti-inflammatory degradation portions upon and after administering. Stated another way, there is no relevant disclosure of critical sequence/amino acids/patterns across the breadth of possible modifications to provide the activity or activities balance to achieve the claimed methods’ effects.
Please note that per pages 16-17 of the specification, even claim 2’s “limiting” to one of four types/classes of “active fragments” is not limited to the full, unmodified sequences of C, FBAC, BACD, and CDE sequences, in that each of these “may comprise an amino acid sequence having 70% or more … sequence homology with the amino acid sequence” of each of these (homology here understood and interpreted to mean identity for the purposes of examination at this time). No guidance is given as to what needs to be maintained, nor what can be removed or modified. There is a clear lack of possession for the broad genera of claim 2’s granulin domain combinations beyond the specific three sequences that were evaluated.
The importance of structure/function correlations has been highlighted by the courts (Abbvie Deutschland v. Janssen Biotech and Centorcor Biologics, App. No. 2013-1338, -1346 (Fed. Cir. , July 1, 2014)). The Abbvie case involved antibodies and written description. The court stated: “We have held that “a sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Id. at 1350 (quoting Eli Lilly, 119 F.3d at 1568– 69).”. The courts then further stated: “With the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus.” (emphasis added) and then state: " Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011).
In the instant case, one could not visualize or recognize a sufficient number of species representative of the claimed genus with the property as claimed. This is particularly the case at least because only three subsequences are disclosed and evaluated, the genus of claim 1 is potentially very large, the genus of claim 2 also is potentially very large though not as large as that of claim 1, the genus of claim 3 – given that “an amino acid sequence” is interpreted to encompass any shorter sequences, down to a dipeptide, along the lengths of SEQ ID Nos. 1-5, as well as these full-length sequences, also is potentially very large, dependent claims 4-8 do not further elucidate structures required for activity, claim 12 includes SEQ ID NO:6, encoding the C domain of PGRN, so that given the comprising open transition any of a very large number of fragments are potentially encompassed (including amino acids to one or both sides of the C domain, please note that this basis of argument also applies to SEQ ID Nos. 7-10), and finally claim 13 also does not further elucidate structures required for activity.
Further regarding claims 6 and 7, there is no indication of possession of specific sequence requirements of the active fragments, other than those three that were evaluated, to meet any of these limitations. Nor is there sufficient guidance, structure/function relationships or other sufficient disclosure.
(5) Method of making the claimed invention/actual reduction to practice:
The method of making peptides is routine, and not a critical factor in this analysis. The specification describes the production of several peptides and evaluates these, but as set forth herein they are not representative of the claimed genus.
As stated supra, the MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic. It is unquestionable that the instant claims potentially encompass very large genera without providing teachings, guidance, examples sufficient to indicate possession. As part of this, the specification lacks sufficient variety of species to reflect the variance in the genus. While having written description of the three proteins identified as active fragments in the specification, including in drawings and examples, the specification does not provide sufficient descriptive support for the myriad of species embraced by the claims.
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals Appellant hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”) Accordingly, it is deemed that the specification fails to provide adequate written description for the genera of the claims under examination and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Claims 1-8, 12, 13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for inhibiting fibrosis in a mouse model when administering full-length PRGN, and the proteins of SEQ ID Nos: 2-4, does not reasonably provide enablement for the claimed methods that include administering any of potentially large genera of active fragments of PRGN to treat a range of pulmonary or airway fibrosis diseases The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one
considers the following factors to determine whether undue experimentation is required (also recited in
MPEP 2164.01(a)): (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the
prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of
direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of
experimentation needed to make or use the invention based on the content of the disclosure. Some
experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
The factors are summarized and analyzed below:
(A) The breadth of the claims:
The claimed “pharmaceutically effective amount of a pharmaceutical composition” of claim 1 that is administered in its method of treating a pulmonary or airway fibrosis disease that comprises both “a progranulin (PGRN) protein or an active fragment thereof as an active ingredient; and a vector comprising a polynucleotide encoding the progranulin (PGRN) protein or an active fragment thereof as an active ingredient thereof, or a cell comprising the vector” encompasses a large and potentially diverse genus of proteins, peptides and polynucleotides in vectors or cells, with the active fragments, at least, having some activity. The subgenus of PGRN proteins does not explicitly require activity, however it is implied that these must have some beneficial effect to treat a pulmonary or airway fibrosis disease at least given the limitation that they be administered in a “pharmaceutically effective amount.” No specific sequence or structural requirements, such as a core sequence, or core sequences, are required in claim 1, and there remains broad scope of possible sequences/structures in the remaining claims.
Please note also that the forms of administering are broad, and include administering as components of food, as a food additive, see pages 29-30.
(B) The nature of the invention: therapeutic for treating subjects.
(C) The state of the prior art
Wang et al., Protein Cell 2015, 6(11):792–803, teaches that PGRN is a 593-amino-acid autocrine growth factor that contains seven-and-a-half repeats of a cysteine-rich motif (CX5-6CX5CCX8CCX6CC XDX2HCCPX4CX5-6C) in the order P-G-F-B-A-C-D-E where A-G are full repeats and P is a half-motif, and inter alia that PGRN blocks the TNF-α induced respiratory burst in neutrophils (and has other anti-inflammatory effects), in contrast to granulin degradation products of PGRN, such that, for example, “The balance between anti-inflammatory PGRN and pro-inflammatory degraded granulin units is also important in neuroinflammation,” page 792. Wang extensively analyzes contradictory results in the field regarding progranulin/TNFR interactions, and on pages 798-799 teaches that “The importance and validity of PGRN-TNFR interactions in inflammatory diseases and conditions are supported by more recent experimental and epidemiological evidences. In addition to musculoskeletal disorders, including inflammatory arthritis (Tang et al., 2011; Tian et al., 2014b), osteoarthritis (Zhao et al., 2014) and bone healing (Zhao et al., 2013a), PGRN was also reported to play an important role in other common inflammatory diseases (Table 1).”
Wang also teaches the following, “The domains of PGRN required for binding to TNFR were then determined through a series of PGRN deletion mutants and three fragments composed of granulin F, A, C and their adjacent linkers were found to be responsible for the binding to TNFR. These three fragments most likely mimic the trimer structure of TNF when binding to TNFR (Wu and Siegel, 2011). Based on these results, Tang et al. further generated an engineered molecule called Atsttrin that only contained half Grn F, A, C, and was found to still bind to TNFR. Atsttrin was shown to have even better therapeutic effects than PGRN in treating inflammatory arthritis (Tang et al., 2011). In brief, this unexpected discovery of PGRN-TNFR interaction provided the molecular insights into the mechanism underlying PGRN mediated anti-inflammatory activities and might present PGRN and its engineered derivative, Atsttrin, as the next generation drug target for various kinds of inflammatory diseases (Liu, 2011; Liu and Bosch, 2012; Sfikakis and Tsokos, 2011; Wu and Siegel, 2011).”
The binding of Atsttrin to TNFR was studied also in Liu et al., PLOS ONE, March 2014 | Volume 9 | Issue 3 | e92743, 8 pages, this however focusing on the therapeutic action in inflammatory arthritis for this specific active derivative of PGRN.
Also, WO 2012/122464 A1, published 9/13/12 (Liu), provided in 3/20/25 IDS so copy not provided, teaches and evaluates a known shortened form of human progranulin (PRGN) identified as Atsttrinα, corresponding to SEQ ID NO:2 in Liu, and three variants of this protein designated by α(plus a number), see paras 76-77, those variants corresponding to SEQ ID Numbers 3-5. These do not include the “B” motif.
(D) The level of one of ordinary skill and (E) The level of predictability in the art
The level of skill in the art is high, however the predictability in the relevant art, as to PGRN and its degradation products – granulins, is not high such that there is a high level of unpredictability with regard to the pro- vs. anti-inflammatory activities of the genus of fragments that could be included in the claims. See inter alia teachings of prior art references set forth above.
(F) The amount of direction provided by the inventor and (G) The existence of working examples
The instant specification teaches and evaluates full length PRGN and specific-sequence fragments it identifies as FBAC, BACD, and CDE, and also claims C by itself.
Other than teaching and evaluating the three specific-sequence fragments, FBAC corresponding to SEQ ID NO:2 with 333 amino acids, BACD corresponding to SEQ ID NO:3 with 305 amino acids, and CDE corresponding to SEQ ID NO:4 with 242 amino acids, there are no substantive detailed disclosures of what subsequence, linkers, or portions must be retained in “active” fragments, nor what must be avoided in fragments to avoid anti-inflammatory degradation portions upon and after administering. Stated another way, there is no relevant disclosure of critical sequence/amino acids/patterns across the breadth of possible modifications to provide the activity or activities balance to achieve the claimed methods’ effects.
Please note that per pages 16-17 of the specification, even claim 2’s “limiting” to one of four types/classes of “active fragments” is not limited to the full, unmodified sequences of C, FBAC, BACD, and CDE sequences, in that each of these “may comprise an amino acid sequence having 70% or more … sequence homology with the amino acid sequence” of each of these (homology here understood and interpreted to mean identity for the purposes of examination at this time). No guidance is given as to what needs to be maintained, nor what can be removed or modified.
Please also note that no teachings are provided for how to avoid degradation in the intestinal tract, nor transport from its lumen into the blood stream and to the site for treatment (lungs, bronchi), of the proteins/active fragments, as well as the vectors/cells that are administered as “food additives.”
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Also, regarding claim 8, given the number and diversity of the “one or more mutants selected from the group consisting of fibronectin, NFkB, COL1A1 and F-actin,” it would take an undue amount of experimentation to achieve what is claimed in the claim method further limited by claim 8.
More generally, given the known opposing properties of full-length PRGN and its degradation domains, see above, the paucity of examples and teachings, and the possible scope of “active fragments” in all of the claims, and the unlimited forms of administering including as food additives, the quantity of experimentation needed to make or use the invention based on the content of the disclosure would be clearly excessive and undue.
Accordingly, claims 1-8, 12 and 13 are rejected under this section.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 4, 6 and 7 are rejected because
They appear to further limit the method of claim 1 by adding functional limitations without setting forth the structure/sequence required for such additionally claimed functional limitations; and
It is unclear whether these additionally recited functional limitations are inherent in (are always met by) the claim 1 compositions (if they are, then these claims would not further limit the compositions of claim 1). Given the claim 1 treating a
Claims 4, 6 and 7 are 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. This rejection stands if all of the species of compositions of claim 1 meet each respective limitation of each of claims 4, 6 or 7, in which case such dependent claim is not further limiting. 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.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 3-6, 13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 20100298232 A1, Liu, published 11/25/2010 (Liu).
Claim 1 is directed to a method of treating a pulmonary or airway fibrosis disease, comprising:
administering to a subject in need thereof a pharmaceutically effective amount of a pharmaceutical composition comprising:
a progranulin (PGRN) protein or an active fragment thereof as an active ingredient; and
a vector comprising a polynucleotide encoding the progranulin (PGRN) protein or the active fragment thereof, or a cell comprising the vector.
Liu teaches Granulin/epithelin precursor (GEP), also known as PC-cell-derived growth factor (PCDGF), acrogranin, progranulin (PGRN), and peptide portions developed therefrom, including atsttrin, Granulin/epithelin precursor (GEP), also known as PC-cell-derived growth factor (PCDGF), acrogranin, progranulin (PGRN), paras 6-22.
Liu teaches these for administration to treat inflammatory diseases and conditions, including inflammatory lung diseases, chronic obstructive pulmonary disease, Abstract.
Liu teaches administering therapeutically effective amounts, see paras 130-135, these disclosed in various embodiments to comprise pharmaceutically acceptable carriers and the like, see paras 132-135 for example, so reasonably and as understood in the art these are taught to be administered in pharmaceutically effective amounts.
Liu teaches therapeutic compositions useful for the therapeutic methods of the invention, these including GEP peptides, including atsttrin, which may be formulated in various ways, paras 126-143, and additionally teaches a polynucleotide encoding the GEP, GEP peptide(s) and/or atsttrin may be particularly included within a vector, para 144, see also through para 154.
The combination of a GEP peptide, including atsttrin, in a therapeutic pharmaceutical composition to be administered for treatment of one or more inflammatory diseases and conditions, including inflammatory lung diseases, chronic obstructive pulmonary disease, where such composition also (additionally) comprises a vector comprising a polynucleotide that encodes such GEP peptide, is at once envisaged.
At least because atsttrin is an active fragment of PRGN, based on the above, Liu anticipates claims 1, 4, 5, 6 (at least based on (i) given the stated anti-inflammatory mechanisms and activities), and 13 (see para 154 regarding plasmid). Please also see claims 1, 8, and 14-17.
Liu also anticipates claim 3 based on the interpretation of “an amino acid sequence” to be as short as any dipeptide of any of SEQ ID Nos. 1-5, this including SEQ ID NO:5, full length PRGN, with which atsttrin shares many lengths of domains so multiply meeting (having multiple matching portions of dipeptides or longer sections) the requirements of claim 3.
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.
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.
Claim(s) 1, 3-8, 12, 13 are rejected under 35 U.S.C. 103 as being unpatentable over Chiba et al., Am J Physiol Lung Cell Mol Physiol 314: L214-223, 2018, provided in IDS, in view of Lin et al., Scientific Reports, (2019) 9:19643, 11 pages (Lin).
Claim 1 is directed to a method of treating a pulmonary or airway fibrosis disease, comprising:
administering to a subject in need thereof a pharmaceutically effective amount of a pharmaceutical composition comprising:
a progranulin (PGRN) protein or an active fragment thereof as an active ingredient; and
a vector comprising a polynucleotide encoding the progranulin (PGRN) protein or the active fragment thereof, or a cell comprising the vector.
Chiba teaches intranasal administration of recombinant progranulin (=PRGN) inhibits bronchial smooth muscle hypertensiveness in mouse allergic asthma, Title. This PRGN blocked TGFα induced upregulation of RhoA I in human bronchial smooth muscle cells, Figs. 1 and 2, and inhibited the antigen-induced upregulation of Ccl2 expression regulated by TNFα/NFkB signaling in airway smooth muscle cells, Fig. 5. Incubation of human bronchial smooth muscle cells with PRGN inhibited both the activation of NFkB and RhoA upregulation induced by TNFα, Fig. 1, p. 220. As administered in the examples Chiba demonstrates administering pharmaceutically effective amounts.
Please note that asthma is disclosed by applicant and claimed in instant claim 5 to be a pulmonary or airway fibrosis disease.
Chiba does not teach also administering with its full length PRGN a vector comprising a polynucleotide encoding the progranulin (PGRN) protein or the active fragment thereof, or a cell comprising the vector.
The level of ordinary skill in the art is high.
Lin teaches gene therapy, involving administering a plasmid comprising a DNA polynucleotide that encodes a protein of interest for inhibiting inflammasome activation to protect from bleomycin-induced pulmonary fibrosis, pages 1-2. Lin teaches that its gene transfer downregulates inflammasome activity and protects from subsequent bleomycin-mediated pulmonary fibrosis, Abstract.
It would have been obvious to supplement the administering of a protein with a vector that comprises a polynucleotide that encodes such protein, in order to provide additional therapeutic effectiveness, this including an extended period of providing such protein given the extended time of expression from such vector. The rationale is applying a known technique to a known device (method, or product) ready for improvement to yield predictable results. Chiba contains and taught base methods of administering PRGN protein upon which the claimed invention can be seen as an improvement, by combining with this protein a vector comprising a polynucleotide encoding the progranulin (PGRN) protein. Lin teaches administering a vector comprising a polynucleotide that encodes a protein that also is shown effective to reduce fibrosis in the same model applicant employed, although this protein is not PRGN or a variant or active fragment thereof. However, the technique of administering a vector that comprises a polynucleotide that encodes a desired protein, such as that taught by Chiba, would reasonably provide the same protein through processes internal to the subject, and would reasonably extend the time period for presence of such protein in the subject. As such, Lin taught a known technique applicable to the methods and compositions of Chiba. Given the high level of ordinary skill in the art, one of ordinary skill in the art would have recognized that applying the known technique would have yielded predictable results and resulted in an improved method of treatment. There would have been a reasonable expectation of success given the level of ordinary skill in the art combined with the respective teachings of the references.
Accordingly, claims 1, 3, 4, 5, 6 (at least based on (i) given the stated anti-inflammatory mechanisms and activities), 7, 12 and 13 would have been obvious.
As to claim 8, the rejection of this claim is based on the rejection of claim 1 given that the “for treating …” merely indicates intended use, and also, alternatively 1) based at least on expected effectiveness in a patient having any such mutation that results in less activities related to the listed group, and secondarily 2) based on effectiveness at least to a de minimis degree when activities of the group are elevated so favoring fibrosis and/or inflammation.
Claim(s) 1, 3-8 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2012/122464 A1, published 9/13/12 (Liu), provided in 3/20/25 IDS so copy not provided, in view of Lin et al., Scientific Reports, (2019) 9:19643, 11 pages (Lin).
Claim 1 is directed to a method of treating a pulmonary or airway fibrosis disease, comprising:
administering to a subject in need thereof a pharmaceutically effective amount of a pharmaceutical composition comprising:
a progranulin (PGRN) protein or an active fragment thereof as an active ingredient; and
a vector comprising a polynucleotide encoding the progranulin (PGRN) protein or the active fragment thereof, or a cell comprising the vector.
Liu teaches and evaluates a known shortened form of human progranulin (PRGN) identified as Atsttrinα, corresponding to SEQ ID NO:2 in Liu, and three variants of this protein designated by α(plus a number), see paras 76-77, those variants corresponding to SEQ ID Numbers 3-5, and also teaches and claims to treat disease caused by or resulting from TNR signaling administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising any of SEQ ID Nos. 3-8, claim 12. Liu further teaches and claims these are administered in the treatment of inflammatory diseases such as chronic obstructive pulmonary disease and inflammatory lung diseases, see claim 14. These sequences fall within the scope of claim 1, as active fragments, and in that they counteract such TNF signaling would reasonably reduce inflammation and resultant fibrosis in the lungs and bronchi. Please also note that per para 20 of the instant corresponding PGPUB No. US 20240009267 A1 chronic obstructive pulmonary disease is listed among pulmonary or airway fibrosis diseases, and also see instant claim 5 listing chronic obstructive pulmonary disease, so that Liu clearly teaches treating what is encompassed by claim 1.
Liu thus teaches and claims (see claims 12 and 14) administering a pharmaceutically effective amount of PRGN active fragments to treat what is encompassed by claim 1, however does not teach also administering in its administered pharmaceutical compositions a vector comprising a polynucleotide encoding the progranulin (PGRN) protein or the active fragment thereof, or a cell comprising the vector.
The level of ordinary skill in the art is high.
Lin teaches gene therapy, involving administering a plasmid comprising a DNA polynucleotide that encodes a protein of interest for inhibiting inflammasome activation to protect from bleomycin-induced pulmonary fibrosis, pages 1-2. Lin teaches that its gene transfer downregulates inflammasome activity and protects from subsequent bleomycin-mediated pulmonary fibrosis, Abstract.
It would have been obvious to supplement the administering of a protein with a vector that comprises a polynucleotide that encodes such protein, in order to provide additional therapeutic effectiveness, this including an extended period of providing such protein given the extended time of expression from such vector. The rationale is applying a known technique to a known device (method, or product) ready for improvement to yield predictable results. Liu contains and taught base methods of administering PRGN protein portions (active fragments) upon which the claimed invention can be seen as an improvement, by adding to the pharmaceutical composition a vector comprising a polynucleotide encoding the progranulin (PGRN) protein or the active fragment thereof, or a cell comprising the vector. Lin teaches administering a vector comprising a polynucleotide that encodes a protein that also is shown effective to reduce fibrosis in the same model applicant employed, although this protein is not PRGN or a variant or active fragment thereof. However, the technique of administering a vector that comprises a polynucleotide that encodes a desired protein, such as those taught by Liu, would reasonably provide the same protein through processes internal to the subject, and would reasonably extend the time period for presence of such protein in the subject. As such, Lin taught a known technique applicable to the methods and compositions of Liu. Given the high level of ordinary skill in the art, one of ordinary skill in the art would have recognized that applying the known technique would have yielded predictable results and resulted in an improved method of treatment. There would have been a reasonable expectation of success given the level of ordinary skill in the art combined with the respective teachings of the references.
Accordingly, claims 1, 4 (based on reducing, so inhibiting, inflammation), 5, and 13 would have been obvious.
Given that all that is required to meet claim 3 is that a dipeptide of any of SEQ ID Nos. 1-5 match a dipeptide of an administered sequence of Liu, and that there are multiple extensive overlaps between Liu SEQ ID NO:3, for example, and instant SEQ ID NO:5 (full length hPRGN), claim 3 would have been obvious.
Assuming all species that meet claim 1’s limitations also meet those of claims 4, 6 and 7 (see 35 USC 112b and 112d rejections above), claims 4, 6 and 7 would have been obvious.
As to claim 8, the rejection of this claim is based on the rejection of claim 1 given that the “for treating …” merely indicates intended use, and also, alternatively 1) based at least on expected effectiveness in a patient having any such mutation that results in less activities related to the listed group, and secondarily 2) based on effectiveness at least to a de minimis degree when activities of the group are elevated so favoring fibrosis and/or inflammation.
Conclusion
No claim is allowed.
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/JOSEPH FISCHER/Primary Examiner, Art Unit 1658
