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 .
Examiner’s Note
This Office Action supersedes the action mailed on 7/28/2026. The prior Office Action had the shortened statutory period for reply set at two months; however, as pointed out by Applicant’s representative, Mr. Darren Haber, the statutory period for reply has been updated on the PTO-326. Therefore, the current Office Action includes the SHORTENED STATUTORY PERIOD FOR REPLY IS SET TO EXPIRE 3 MONTHS FROM THE MAILING DATE OF THIS COMMUNICATION. The outstanding rejections remain unchanged.
Election/Restrictions
Applicant's election with traverse of Group I (Claims 1 and 8-18), and Species (i) exemplified by SEQ ID NO: 10, in the reply filed on July 1, 2026) is acknowledged. The traversal is on the ground(s) that the Examiner failed to follow proper guidelines to issue the restriction requirement on the basis that applications filed under PCT are required to follow the rules according to 37 CRF 1.475(a)-(b) and that (a) Unity of Invention Exists Between Group I and Group II. Further, Applicant argues that under the rules of Unity of Invention, the Examiner failed to show a common technical feature that is not novel or obvious over the prior art, and the applicant affirms (b) the Elected Species Possesses a Special Technical Feature That Defines a Contribution Over the Prior Art. Applicant further traverses on the grounds that the Prior Art (i) Fails to Teach or Suggest Specific Combination of Mutations and (ii) the Prior Art Teaches Away From the Claimed Solution. These arguments are not found persuasive.
As set forth in the prior Restriction Requirement, the claims recite both a product (Group I, Claims 1-18) and process of use (Group II, Claims 19 and 23). Each group can be classified into distinct categories.
The distinct classification alone are enough to indicate search burden. Inventions can be shown to be distinct if either or both of the following can be shown: (1) the process for using the product as claimed can be practiced with another materially different product or (2) the product as claimed can be used in a materially different process of using that product. See MPEP § 806.05(h). In the instant case, the process as claimed of treating or reducing the blood sugar level and type 2 diabetes can be achieved by lifestyle modification comprising physical activity, dietary changes and weight management.
Restriction for examination purposes as indicated is proper because all the inventions listed in this action are independent or distinct for the reasons given above. Additionally, there would be a serious search and/or examination burden if restriction were not required because one or more of the following reasons apply: 1) The inventions have separate statuses in the art in view of their different classification, 2) the inventions have separate statuses in the art due to their divergent subject matter, and 3) the inventions require different search queries. Each of these listed reasons require search of several different inventive concepts, and each invention is likely to raise different issues under 35 USC 101 and 112, first paragraph.
Regarding (i) and (ii), US’416 discloses FGF1 mutant proteins, which include an N-terminal deletion, point mutation(s), or combinations; in some examples, the mutant FGF1 proteins have reduced mitogenic activity; and the disclosed FGF1 mutants can reduce blood glucose in a mammal, and Yampolsky et. al. teach about the exchangeability of amino acids in proteins and predicted the effects of amino acid exchanges; see Art Rejections and Prior Art Cited below for more.
The requirement is still deemed proper and is therefore made FINAL.
Applicant’s election with traverse of the species SEQ ID NO: 10 in the reply filed on July 1, 2026 is acknowledged. The species of group I, therefore claims 1 and 8-18 which read on the elected species has been considered. Claims 1 and 8-18 are hereby examined on the merits.
Claims 19 and 23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 1, 2026.
Priority
This application is a 371 of PCT/PL2022/050032, filed May 25, 2022. This application claims priority to POLAND P.438001, filed May 26, 2021.
Status of Claims
Claims 1-19 and 23 were filed November 27, 2023. Claims 1, 8, and 11 were amended, and claims 2-7 were cancelled on July 1, 2026. Claims 19 and 23 are withdrawn for further consideration. Claims 1 and 8-18 are currently examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 11/27/2023 and 7/1/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
(i) The disclosure is objected to because it contains embedded hyperlinks and/or other form of browser-executable codes. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term New England Biolab, Thermo Fisher Scientific, which is a trade name or a mark used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as Inc. following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
(ii) The single letter code of amino acids in the Specification is represented incorrectly. For example, lysine (see page 9, line 16) should be represented by “K”.
Appropriate correction is required.
Claim Objections
Claims 1, 8, 12, 17 and 18 are objected to because of the following informalities: amino acid sequence number is not represented in standard form. For example, protein sequence/amino acid sequence numbers should be represented as SEQ ID NO: 10.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (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 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 1, 8-12 are rejected under 35 U.S.C. 103 as being unpatentable over US 20190151416 (published May 23, 2019, cited in IDS filed on 11/27/2023), in view of Pellegrini et. al. (“Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin”; Luca Pellegrini, David F. Burke, Frank von Delft, Barbara Mulloy & Tom L. Blundell; Sci. Nature, volume 407, pages 1029–1034; published October 26, 2000).
US’416 discloses that mutated FGF1 proteins; their use, for example to reduce blood glucose and/or to treat a metabolic disease; and these mutants have significantly reduced mitogenicity (see [0002]). US’416 further disclosed that mutated FGF1 proteins containing an N-terminal truncation, one or more point mutation(s) (such as amino acid substitutions, deletions, additions, or combinations thereof), or combinations of N-terminal deletions and point mutation(s); in some examples, such mutated FGF1 proteins have reduced mitogenicity relative to mature FGF1 (see [0006]). US’416 teaches SEQ ID NO: 2 provide an exemplary human FGF1 protein sequence; Source: GenBank Accession Nos: BC032697.1 and AAH32697.1; Heparan binding residues are amino acids 127-129 and 133-134 (see [0017]). US’416 provides exemplary mutations that can be made to a mutant FGF1 protein, with amino acids referenced to either SEQ ID NOS: 2 or 5. One skilled in the art will recognize that these mutations can be used singly, or in any combination (such as 1-19, 1-10, 4-8, 2-7, 5-25, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 of these amino acid substitutions and/or deletions) (see [0082]). US’416 teaches mutations can also be introduced to affect the stability and receptor binding selectivity of the protein (see [0109]) and specifies mutations below are noted by a particular amino acid for example in SEQ ID NOS: 2 or 5, one skilled in the art will appreciate that the corresponding amino acid can be mutated in any FGF1 sequence; for example, Q40 of SEQ ID NO: 5 corresponds to Q55 of SEQ ID NO: 2 (see [0111]).
US’416 lists the mutations in TABLE 1 (see [0083]) below - Exemplary FGF1 mutations
Location of Point
Location of Point
Mutation Position
Mutation Position
in SEQ ID NO: 2*
Mutation Citation
in SEQ ID NO: 5
Q55
Q40P
Q40
S62
S47I
S47
H108
H93G
H93
S114
S99A
S99
Note: * SEQ ID NO: 2 of the US’416 has the same amino acid (AA) sequence as well as the AA# as the wild-type FGF-1 protein sequence as shown in SEQ ID NO: 1 or AA# in SEQ ID NO: 10 in the instantly claimed invention. Therefore, S114 corresponds to S99, Q55 corresponds to Q40, S62 corresponds to S47, and H108 corresponds to H93 with the blue AA# corresponding to SEQ ID NO: 5 of US’416.
US’416 discloses the isolated mutated mature FGF1 protein comprises one or more point mutations selected from the group consisting of: K12V, H21Y, Q40K, ….. S47I, … H93G, .. (see claim 4); wherein the isolated mutated mature FGF1 protein comprises mutations at one or more of S99, K101, H102, and W107 (see claim 5); the combination Q40P, S47I, and H93G (see [0004]); wherein the mutated mature FGF1 protein comprises the protein sequence of SEQ ID NO: 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 (see claim 8); wherein the N-terminal amino acid is a methionine (see claim 9); wherein the protein has decreased mitogenicity compared to a native mature FGF1 protein (see claim 10); wherein the protein has increased blood glucose lowering ability compared to a native mature FGF1 protein (see claim 11); provides an exemplary N-terminally truncated form of FGF1 with four point mutations (Q40P, S47I, H93G, and N95V) (see [0029] SEQ ID NO: 16); provides an exemplary mature form of FGF1 with four point mutations (S99A, K101E, H102A, and W107) (see [0038] and SEQ ID NO: 25). Regarding SEQ ID NO: 25, US’416 specifies one, two, three of all four of these point mutations can be made to an FGF1 sequence (such as a mutant FGF1 protein provided herein) to reduce its mitogenicity (see [0038]). US’416 also specify exemplary mutations that can be used to increase the thermostability include one or more of Q40P, S47I, H93G, and N95V (see [0080]).
However, US’416 is silent about the addition of mutation L150D.
Pellegrini et. al. teaches the structure of the FGF1-FGFR2-heparin ternary complex provides a structural basis for the essential role of heparan sulphate in FGF signalling; where the complex is assembled around a central heparin molecule linking two FGF1 ligands into a dimer that bridges between two receptor chains (see Abstract). Pellegrini et. al. teaches the total surface area buried at the protein-heparin interface is large at with FGF1 and with domain D2 (FGFR2 domain), van der Waals contacts contribute substantially to the protein-heparin interactions (see page 1029, right col, paragraph 3). Pellegrini et. al. further teaches, the structure of the ternary complex, heparin links two FGF1 molecules into a dimer that lacks a protein-protein interface, but with significant differences in the relative orientation of FGF and heparin. (see page 1029-1030, right col, paragraph 4). Pellegrini et. al. discloses conserved Trp 107 is central to this new heparin-binding site, and an FGF2 mutant, in which the tryptophan residue was mutated to alanine, showed unaltered affinity for the receptor, but a marked reduction in mitogenic potency (see page 1030, right col, Fig. 2c).
Pellegrini et. al. elaborates the protein-protein interactions in the ternary complex are dominated by ligand binding of each receptor chain; FGF1 binding to the receptor involves contacts with D2 domain, the linker region and FGFR2 (D3 domain), which create a continuous interface burying a total of 1,700 A2 surface area; which is consistent with biochemical evidence that narrows the minimal ligand-binding region of FGFR to a fragment comprising D2, the interdomain sequence and an amino terminal sequence of D3 (see page 1033, left col, paragraph 3).
Pellegrini et. al. specifies contacts between FGF1 and domain D2 are predominantly hydrophobic and involve residues Tyr 15, Gly 20, Phe 22, Tyr 94, Leu 133 and Leu 135 of the ligand, and residues Lys 164, Leu 166, Ala 168, Val 169 and Pro 170 of D2 (see page 1033, left col, paragraph 3). Pellegrini et. al. also teaches that the linker between D2 and D3, the guanidinium moiety of invariant Arg 251 is surrounded by three hydrophobic FGF1 residues,
Leu 89, Leu 133 and Pro 134, and is hydrogen bonded to the main chain of FGF1 His 93; these interactions immobilize the arginine side chain in the correct position to form a crucial hydrogen bond with the conserved Asn 95 (or N95)of FGF1 (see page 1033, left col, paragraph 3, Fig. 4a)
Examiner’s Note: Mutation of Leu 135 (L150 in the instant claim) to a charged residue, for example Asp would disrupt the hydrophobic interaction. This is in direct correlation with the instantly claimed invention which states that guided by the insight into the structure of the FGF1 protein, the inventors have designed and have obtained an FGF1 mutein with reduced ability to bind to FGFR 1-4 receptors. The inventors have achieved this by replacement Leu150Asp (L150D), a well-known amino acid residue responsible for direct physical interaction with FGFR. A reduction of binding affinity to the FGFR leads to reduction of mitogenic potential of the protein (see instant specification page 17, line 3-7).
Examiner’s Note: Mutation of Asn 95 to Val (N95V) as taught in US’416 (underlined above) might disrupt the hydrogen bond with Arg 251 as illustrated in Fig. 4a by Pellegrini et. al.); yet will stabilize the hydrophobic core formed by Leu 89, Leu 133 and Pro 134 due to the insertion of Val.
Examiner’s Note: The instantly claimed amino acid residue #s S114 corresponds to S99, Q55 corresponds to Q40, S62 corresponds to S47, H108 corresponds to H93, and L150 corresponds to L135 of US’416 and Pellegrini et. al.
At the time before the effective filling date of the claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to introduce point mutations in the mutant FGF1 protein sequence to decrease mitogenicity, increase stability, alter binding affinity for heparin and/or heparan sulfate (compared to the portion of a native FGF1 protein without the modification), or combinations (see US’416 [0104]) as taught by US’416, along with appropriate modifications with addition of mutations such that the binding has unaltered affinity for the receptor, but a marked reduction in mitogenic potency (see Pellegrini et. al. page 1030, right col) as taught by Pellegrini et. al., to arrive at the presently claimed invention. One of skill in the art would appreciate that the method for producing a human fibroblast growth factor 1 (FGF-1) mutein with decreased mitogenicity could be achieved by mutating, Leu 135 (L150 in the instant claim) to a charged residue Asp (D) that would disrupt the hydrophobic interaction; which in turn might block receptor binding and mitogenic activity (as taught by Pellegrini et. al.). The artisan of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in producing FGF-1 muteins with reduced mitogenic activity and enhanced thermodynamic stability with an expectation to achieve excellent glucose lowering therapeutic composition.
Regarding claim 1: US’416 discloses the isolated mutated mature FGF1 protein, wherein the protein has decreased mitogenicity compared to a native mature FGF1 protein (see claim 10); wherein the protein has increased blood glucose lowering ability compared to a native mature FGF1 protein (see claim 11); mutations that can be used to increase the thermostability include one or more of Q40P, S47I, H93G, and N95V (see [0080]); exemplary mature form of FGF1 with four point mutations (S99A, …..to reduce its mitogenicity (see [0038]). Pellegrini et al. teaches the FGF1 binding to the receptor; and contacts between FGF1 and receptor domain are predominantly hydrophobic and involve residues …Leu 135 of the ligand (see page 1033, left col, paragraph 3) [implying Leu 135 which corresponds to L150 in the instantly claimed invention is one of the crucial amino acid residues that is required for hydrophobic interaction].
Regarding claims 8 and 12: As taught above by US’416 and including the isolated mutated mature FGF1 protein comprises one or more point mutations selected from the group consisting of: K12V, H21Y, Q40K, L44F, S47A, S47V, S47I, Y55F, Y55V, Y55S, Y55A, Y55W, A66C, C83T, C83S, C83A, C83V, E87Q, E87D, E87V, E87A, E87S, E87T, E87H, H93G, H93A, N95V, N95A, N95S, N95T, S99A, K101E, H102Y, H102A, W107A F108Y, S116R, C117V, C117P, C117T, C117S, C117A, and F132W wherein the numbering refers to the sequence shown SEQ ID NO: 5. (see claim 4); the isolated mutated mature FGF1 protein comprises mutations at one or more of S99, K101, H102, and W107, wherein the numbering refers to SEQ ID NO: 5. (see claim 5).
Regarding claims 9-11: US’416 teaches the mutant FGF1 protein can include for example deletion of at …. least 19 consecutive N-terminal amino acids; in some examples, the mutant FGF1 protein includes point mutations, such as one containing at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 additional amino acid substitutions, such as one or more of those shown in Table 1; in some examples, the mutant FGF1 protein includes both an N-terminal truncation and one or more additional point mutations (see [0006] and Table 1).
Claims 13-18 are rejected under 35 U.S.C. 103 as being unpatentable over US 20190151416 (published May 23, 2019, cited in IDS filed on 11/27/2023) and Pellegrini et. al. (“Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin”; Luca Pellegrini, David F. Burke, Frank von Delft, Barbara Mulloy & Tom L. Blundell; Sci. Nature, volume 407, pages 1029–1034; published October 26, 2000), as previously applied to claims 1 and 8-12 above, and further in view of US 20170355740 (published December 14, 2017, cited in IDS filed on 11/27/2023).
The teachings of US’416 and Pellegrini et. al. are discussed above. US’416 and Pellegrini et. al. do not teach about the dimer of human fibroblast growth factor 1 (FGF-1) muteins connected by a linker, preferably an amino acid linker.
US’740 discloses FGF1 mutant proteins having one or more mutations in the heparin binding domain, mutants may also have an N-terminal deletion, point mutation(s), or combinations thereof; the mutant FGF1 proteins have reduced mitogenic activity; and the FGF1 mutants can reduce blood glucose in a mammal, and in some examples are used to treat a metabolic disorder (see Abstract).
Regarding claims 13-18; US’740 provides an exemplary FGFR1c binding protein sequence that can be attached at its N- or C-terminus directly or indirectly to any of the FGF1 mutants provided herein to generate a chimeric protein. In addition, it can be linked to itself one or more times to generate an FGFR1c multimer, such as a dimer (see [0067-0086]). US’740 specifies linkers can include naturally occurring amino acids, non-naturally occurring amino acids, or a combination of both. In one example a linker is composed of at least 5, at least 10, at least 15 or at least 20 amino acids (see [0119].
It would have been obvious to combine the teachings of US’416, Pellegrini et. al. and US’740, before the effective filing date of the claimed invention to prepare FGF1 protein dimers of low mitogenicity and high stability. One of ordinary skill in the art would have been motivated to do so with an expectation to succeed in producing FGF-1 muteins with reduced mitogenic activity and enhanced thermodynamic stability with an expectation to achieve excellent glucose lowering therapeutic composition.
Therefore, the presently claimed invention was prima facie obvious to one of ordinary skill in the art at the time of the effective filling date.
Prior Art of Record
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Betts et. al. (“Amino Acid Properties and Consequences of Substitutions”, Matthew J. Betts, Robert B. Russell, Bioinformatics for Geneticists, Chapter 14, published February 21, 2003).
Yampolsky et. al. (“The Exchangeability of Amino Acids in Proteins”; Lev Y. Yampolsky and Arlin Stoltzfus; Genetics 170: 1459–1472, published August 2005).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KOYELI BANERJEE whose telephone number is (571)272-5751. The examiner can normally be reached Monday-Friday 8-4PM.
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/KOYELI BANERJEE/Examiner, Art Unit 1658
/Melissa L Fisher/Supervisory Patent Examiner, Art Unit 1658
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