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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 09/03/2025 has been entered.
Change in Examiner
The examiner of your application in the PTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Stephanie Sullivan, Art Unit 1635.
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 09/03/2025 is acknowledged. Claims 1-54,57,62,63,71,72 and 74 were/stand cancelled. No claims were amended. Claims 83 and 84 are new. Claims 55,56,58-61,64-70,73 and 75-84 are pending. Claim 70 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 05/24/2024. Claims 55,56,58-61,64-69,73 and 75-84 are directed to the elected invention and are under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged, and claim for foreign priority under 35 U.S.C. 119 (a)-(d) is acknowledged. This application is a continuation of PCT/EP2019/086019 filed on 12/18/2019, which claims the benefit of Application Nos. EP19208066.1 filed on 11/08/2019 and EP18214221.6 filed on 12/19/2018. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Specification
The use of the terms which are trade names or marks used in commerce, has been noted in this application. Below is a non-exhaustive list of terms identified in the application:
-UniProt, page 18, line 17 (also on pages 22-30 and throughout the specification)
-Agilent Technologies, page 31, line 20
-Invitrogen, page 31, line 20
-Promega, page 31, line 21
-Invivogen, page 31, line 21
Applicant is advised to review the entire specification for trade names or marks used in commerce and correct them appropriately. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM or ® 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.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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. There are numerous instances in the specification reciting an embedded hyperlink and/or browser-executable code. See at least pages 51,102,107-112 . Applicant should review the entire specification and correct all instances of hyperlinks or browser-executable code.
Response to Arguments
Applicant’s arguments, see page 7, filed 09/03/2025, with respect to the amendments to the specification have been fully considered but are not persuasive. Upon review of the amended specification, it appears the above trademarks and tradenames in the specification have not been amended to reflect that they are trademarks or tradenames. Other than stating that applicant submits a substitute specification and that no new matter was added, applicant did not specify what the amendment to the specification pertained to.
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.
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.
Claims 55-56, 58-61, 64, and 77-83 are rejected under 35 U.S.C. 103 as being unpatentable over Guler-Gane, et al. (PLOS ONE, Vol 11 No 5, 19 May 2016) in view of Alonso et. al. (US 2012/0093775; Published: Apr. 19,2012; Effectively filed: Mar. 26, 2010 and Hempstead et. al. (US 2008/0025978 A1; Published: Jan. 31, 2008; Effectively filed: Jul. 27, 2007).
Regarding claim 55, Guler-Gane teaches a composition comprising an expression vector, called “pDest12.20riP CD33 SEAP -FLAGI10His” (page 3, paragraph “Generation of expression vectors”), which encodes a recombinant RNA construct. Further, Guler-Gane teaches that the expression vector encodes a CD33 signal peptide connected to the SEAP gene (page 5, paragraph 2, lines 3-6), which is a first nucleic acid sequence encoding a signal peptide operably linked to a second nucleic acid sequence encoding a protein, wherein the second nucleic acid sequence encoding the protein comprises a coding sequence of a mature protein of the protein. Guler-Gane teaches that by replacing the signal peptide the level of expression of the protein can be modified. Indeed, this has shown to be the case in a number of studies, where replacement of the native signal peptides with those from proteins that are known to secrete at high levels (e.g. luciferase, tissue plasminogen activator) can significantly improve secreted levels, and the potential posed by utilizing heterologous signal peptides from highly secreted proteins to improve protein yields is an attractive one (page 2, bottom).
The specification of the instant application discloses, in reference to human IGF1, that the sequence encoding the mature protein is 70 amino acids (nucleotides 145-354), which is downstream and separate from the sequences encoding the signal peptide and propeptide (page 22, lines 24-30), and additionally, that “the term "mature protein" refers to the protein synthesized in the endoplasmic reticulum and secreted via the Golgi apparatus in a cell expressing and secreting the protein” (page 23, lines 11-12). Guler-Gane uses the same definition of a mature protein in reference to SEAP. They reference that a mature protein is synthesized and processed (signal peptide removed) in the endoplasmic reticulum and secreted via trafficking through the Golgi network (page 2, paragraph 2), and that the SEAP protein linked to the CD33 signal peptide is that of the mature SEAP protein sequence (page 5, paragraph 2).
Guler-Gane also teaches the signal peptide is a signal peptide heterologous to the protein, with the proviso that the protein is not an oxidoreductase. The specification of the instant application defines “signal peptide heterologous to the protein” on page 18, lines 31-33 as “a naturally occurring signal peptide which is different to the naturally occurring signal peptide of the protein, i.e. the signal peptide is not derived from the same gene of the protein.” The CD33 signal peptide and SEAP protein of Guler-Gane are heterologous as the CD33 signal peptide is not the naturally occurring signal peptide of SEAP (page 5, paragraph 2, lines 1-2), and SEAP is a phosphatase (secreted alkaline phosphatase) (page 3, paragraph 1, lines 1-3), which is not an oxidoreductase.
Guler-Gane does not teach a recombinant RNA construct that encodes a protein comprising an amino acid sequence with at least 85% sequence identity to the amino acid sequence encoded by SEQ ID NO: 7 or SEQ ID NO: 8; and wherein the signal peptide is the signal peptide of brain-derived neurotrophic factor (BDNF).
The instant specification discloses that in a preferred embodiment of the present invention the mRNA comprising a nucleic acid sequence encoding human insulin-like growth factor 1 (IGF1) and the signal peptide of the brain-derived neurotrophic factor (BDNF) comprises a nucleic acid sequence transcribed from the DNA sequence as shown in SEQ ID NO: 7 comprises: (i) a nucleic acid sequence encoding the propeptide (also called pro-domain) of human IGF1 having 27 amino acids as shown in SEQ ID NO: 38, (ii) a nucleotide acid sequence encoding the mature human IGF1 having 70 amino acids as shown in SEQ ID NO: 39, and (iii) a nucleic acid sequence encoding the signal peptide of the brain-derived neurotrophic factor (BDNF), preferably, a nucleotide acid sequence encoding the signal peptide of the brain- derived neurotrophic factor (BDNF) as shown in SEQ ID NO: 30 (see page 88,1-14, page 89, lines 3-8).
In addition, Table 1 on page 105 of the specification shows the amino acid sequences, DNA sequences and RNA sequences of each of the signaling peptide and protein for Cpd. No. 4 which is the compound that is claimed. See below:
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78
599
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45
596
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Alonso et. al. discloses a recombinant nucleic acid construct that has 100% sequence similarity to the sequence encoding the propeptide and mature protein of human IGF1 comprised in SEQ ID NO: 7 in the instant application (see alignment below).
Alignment of Instant SEQ ID NO: 7 (Qy) to Alonso’s SEQ ID NO: 2 (Db):
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393
973
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463
804
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Alonso further discloses that such a nucleic acid construct comprising a nucleotide sequence encoding IGF1 presents therapeutic benefits for the treatment of diseases such as cirrhosis [0004]; [0083]; [0053]. Alonso also discloses that it is possible to include a polynucleotide encoding the IGF1 fused to a heterologous signal sequence that is synthetically derived or isolated from another gene that directs the protein into the endoplasmic reticulum from which it is discharged to the appropriate destination [0058]. Therefore Alonso et al. suggests using a heterologous signal sequence with IGF1.
Alonso et. al. discloses a recombinant nucleic acid construct that has 100% sequence similarity to the sequence encoding the propeptide and mature protein of human IGF1 comprised in SEQ ID NO: 8 in the instant application (see alignment below).
Alignment of Instant SEQ ID NO: 8 (Qy) to Alonso’s SEQ ID NO: 2 (Db):
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389
975
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444
805
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Alonso does not disclose a BDNF signal peptide operably linked to a protein of interest and wherein the RNA construct encodes a protein comprising an amino acid sequence with at least 85% sequence identity to SEQ ID NO: 7 or 8.
However, Hempstead discloses an amino acid sequence encoding a signal peptide that has 100% sequence identity to the sequence encoding the BDNF signal peptide in SEQ ID NO: 7 (SEQ ID NO: 30) (See sequence alignment below).
Hempstead further discloses any of the pro-domains described above optionally comprise a signal sequence, and that the signal sequence characteristically includes a stretch of hydrophobic amino acid residues that facilitates transport into the ER and facilitates secretions from cells, and the signal sequences found at the N-terminus of BDNF (SEQ ID NO: 93)…..constitute suitable signal sequences (paragraph 0080).
Alignment of instant SEQ ID NO: 30 to Hempstead’s SEQ ID NO: 93.
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822
753
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It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the composition of Guler-Gane with Alonso’s construct encoding the IGF1 protein and Hempstead’s heterologous BDNF signal peptide. There is a reasonable expectation of success because Alonso teaches that it is possible to fuse IGF1 to a heterologous signal sequence, and therefore an ordinary artisan would be motivated to try any heterologous signal sequence including a signal sequence from BDNF. One would have been motivated to substitute Guler-Gane’s SEAP protein and CD33 signal peptide with Alonso’s IGF1 protein and Hempstead’s BDNF signal peptide because Alonso teaches that IGF1 has therapeutic benefits for diseases such as cirrhosis and that a heterologous signal peptide can be fused to IGF1 to facilitate transport into the endoplasmic reticulum, and facilitate secretion from cells, and because Hempstead teaches the pro-domains may comprise a signal sequence which characteristically includes a stretch of hydrophobic amino acid residues that facilitates transport into the ER and facilitates secretions from cells, and the signal sequences found at the N-terminus of BDNF (SEQ ID NO: 93) constitute suitable signal sequences (paragraph 0080).
Regarding claim 56, the teachings of Guler-Gane, Alonso, and Hempstead as applied to claim 55 are discussed above. Alonso and Hempstead teach nucleic acid construct sequences that have 100% sequence similarity to the SEQ ID: NO 28, SEQ ID NO: 29, and SEQ ID NO: 30 all of which are comprised within SEQ ID NO: 7.
Regarding claim 58 and 61, The teachings of Guler-Gane, Alonso, and Hempstead as applied to claim 55 are discussed above.
Guler-Gane teaches that SEAP is secreted, and that the quantity of secreted SEAP protein using a heterologous CD33-AA signal peptide (the CD33 signal peptide modified by insertion of 2 alanine residues at its C-terminal end) is higher than the quantity of secreted SEAP protein using its natural signal peptide (page 5, paragraph 2, lines 9-16; page 6, Figure 1; page 7, Table 1), which is a “signal peptide homologous to the protein” as defined in the specification of the instant application on page 19, lines 22-24. Guler-Gane also teaches that SEAP is secreted when expressed in a cell, and that the quantity of secreted SEAP protein using a heterologous CD33-AA signal peptide (the CD33 signal peptide modified by insertion of 2 alanine residues at its C-terminal end) is higher than the quantity of secreted SEAP protein using its natural, homologous signal peptide when expressed in a cell (page 5, paragraph 2, lines 9-16; page 6, Figure 1; page 7, Table 1).
Regarding claims 59-60, The teachings of Guler-Gane, and Alonso as applied to claim 55 are discussed above.
Guler-Gane and Alonso do not disclose the composition of claim 55 wherein the signal peptide of BDNF comprises the amino acid sequence of SEQ ID NO: 31.
Hempstead discloses an amino acid sequence encoding a signal peptide that has 100% sequence identity to the sequence encoding the BDNF signal peptide as shown in SEQ ID NO: 31 (see sequence alignment below). Hempstead further discloses the signal sequence facilitates transport into the endoplasmic reticulum, and facilitates the secretion from cells [0080].
Alignment of Instant SEQ ID NO: 31 to Hempstead’s SEQ ID NO: 93.
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682
730
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It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the compositions of Guler-Gane and Alonso with Hempstead’s heterologous BDNF signal peptide. One would have been motivated to substitute Guler-Gane’s and Alonso’s composition with Hempstead’s BDNF signal peptide because Hempstead teaches that a heterologous signal peptide can be fused to IGF1 to facilitate transport into the endoplasmic reticulum, and facilitate secretion from cells. There is a reasonable expectation of success because Alonso teaches that it is possible to fuse IGF1 to a heterologous signal sequence.
Regarding claim 64, the teachings of Guler-Gane, Alonso, and Hempstead as applied to claim 55 are discussed above.
Alonso and Hempstead together teach nucleic acid construct sequences that have 100% sequence similarity to the SEQ ID: NO 28, SEQ ID NO: 29, and SEQ ID NO: 30 all of which together make up SEQ ID NO: 7. It is noted that instant SEQ ID NO: 8 is the RNA sequence that corresponds to the DNA sequence of SEQ ID NO: 7.
Regarding claim 77, and 79-80, the teachings of Guler-Gane, Alonso, and Hempstead as applied to claim 55 are discussed above.
Hempstead discloses an amino acid sequence encoding a signal peptide that has 100% sequence identity to the sequence encoding the BDNF signal peptide comprised in SEQ ID NO: 7 (SEQ ID NO: 30). Hempstead further discloses the signal sequences of the approximately 18 amino acid residues found at the N-terminus of native BDNF (see paragraph [0082]).
Regarding claim 78, the teachings of Guler-Gane, Alonso, and Hempstead as applied to claim 55 are discussed above.
Alonso et. al. discloses a recombinant nucleic acid construct that has 100% sequence similarity to the sequence encoding the propeptide and mature protein of human IGF1 comprised in SEQ ID NO: 7 in the instant application.
Regarding claim 81, the teachings of Guler-Gane, Alonso, and Hempstead as applied to claim 55 are discussed above.
Alonso teaches a nucleotide sequence that is substantially homologous to the nucleotide sequence of the invention can typically be isolated from a producer organism of the polypeptide of the invention based on the information contained in said nucleotide sequence, or it is constructed based on the DNA sequence described above (see paragraph [0064]).
Regarding claims 82-83, the teachings of Guler-Gane, Alonso, and Hempstead as applied to claim 55 are discussed above.
Alonso and Hempstead together teach nucleic acid construct sequences that have 100% sequence similarity to the SEQ ID: NO 28, SEQ ID NO: 29, and SEQ ID NO: 30 all of which together make up SEQ ID NO: 7. It is noted that instant SEQ ID NO: 8 is the RNA sequence that corresponds to the DNA sequence of SEQ ID NO: 7.
See the alignment below, wherein Qy is SEQ ID NO: 7 and Db is SEQ ID NO: 8.
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371
591
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Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the composition of Guler-Gane with Alonso’s construct encoding the IGF1 protein and Hempstead’s heterologous BDNF signal peptide to arrive at the instant claims with a reasonable expectation of success. There is a reasonable expectation of success because Alonso teaches that it is possible to fuse IGF1 to a heterologous signal sequence, and therefore an ordinary artisan would be motivated to try any heterologous signal sequence including a signal sequence from BDNF. One would have been motivated to substitute Guler-Gane’s SEAP protein and CD33 signal peptide with Alonso’s IGF1 protein and Hempstead’s BDNF signal peptide because Alonso teaches that IGF1 has therapeutic benefits for diseases such as cirrhosis and that a heterologous signal peptide can be fused to IGF1 to facilitate transport into the endoplasmic reticulum, and facilitate secretion from cells, and because Hempstead teaches the pro-domains may comprise a signal sequence which characteristically includes a stretch of hydrophobic amino acid residues that facilitates transport into the ER and facilitates secretions from cells, and the signal sequences found at the N-terminus of BDNF (SEQ ID NO: 93) constitute suitable signal sequences (paragraph 0080). As instant SEQ ID NO: 8 is the RNA sequence that corresponds to the DNA sequence of SEQ ID NO: 7, since Alonso and Hempstead teach nucleic acid construct sequences that have 100% sequence similarity to the SEQ ID: NO 28, SEQ ID NO: 29, and SEQ ID NO: 30 all of which are comprised within SEQ ID NO: 7, it would be obvious that the sequences of Alonso and Hempstead would also have 100% sequence similarity to instant SEQ ID NO: 8.
Accordingly the limitations of claims 82-83 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Applicant's arguments filed 09/03/2025 have been fully considered but they are not persuasive.
Applicant argues on page 7 that none of the references teach or suggest using or selecting a BDNF signal peptide for expression of any heterologous protein, much less for expression of IGF-1 as recited in the instant claims. Applicant argues on page 8 that a person of ordinary skill in the art reading the cited references would not have found any teaching, suggestion, or motivation to combine or modify the teachings of Guler-Gane, Hempstead, and Alonso to modify Guler-Gane’s construct encoding CD33 signal peptide and SEAP protein by replacing the SEAP protein with IGF-1 and CD33 signal peptide with BNDF signal peptide at least because Alonso provides a list of suitable examples of heterologous signal peptide that does not include BDNF and Hempstead does not teach or suggest using a construct encoding any protein with a heterologous signal peptide to facilitate secretion of the protein. Applicant argues on page 8 that a skilled artisan would not have arrived at the claimed composition, namely a sequence encoding a BDNF signal peptide linked to a sequence encoding an IGF-1 protein based on the teachings of the above references, and at best would have relied on Alonso teaching a polynucleotide encoding the pro-IGF-1 fused to a heterologous signal sequence can be used and following Alonso, simply used a heterologous signal peptide from “gelsolin, albumin, fibrinogen, among others, the signal peptides from tissue plasminogen activator, insulin, and neuron growth factor” as suggested by Alonso.
This is not found persuasive because Guler-Gane provides motivation for further exploration regarding the potential posed by utilizing heterologous signal peptides from highly secreted proteins to improve protein yields as being attractive (by replacing the signal peptide the level of expression of the protein can be modified. Indeed, this has shown to be the case in a number of studies, where replacement of the native signal peptides with those from proteins that are known to secrete at high levels can significantly improve secreted levels, and the potential posed by utilizing heterologous signal peptides from highly secreted proteins to improve protein yields is an attractive one (page 2, bottom)). Also, Alonso provides the suggestion of using IGF1 with a heterologous signal sequence (it is possible to include a polynucleotide encoding the IGF1 fused to a heterologous signal sequence that is synthetically derived or isolated from another gene that directs the protein into the endoplasmic reticulum from which it is discharged to the appropriate destination [0058]), with Hempstead teaching suitable BDNF signal peptides. Therefore, since Hempstead teaches the signal sequence facilitates transport into the endoplasmic reticulum, and facilitates the secretion from cells [0080] and that BDNF signal peptides are suitable, which is the same desire as the signal peptides of Alonso, there would be a reasonable expectation of success and sufficient motivation. Regardless of whether there are other equally obvious heterologous signal peptides to be used, the use of the BDNF signal peptide is not any less obvious Regarding applicant’s argument about the suggested signal peptides of Alonso, this is not found persuasive because the rejection is made under 103 and does not need to exemplify all embodiments, only suggest. “Disclosed examples and preferred embodiments do not constitute a teaching away from the broader disclosure or non-preferred embodiment.” In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). MPEP 2123. Therefore, the specific signal peptides that are considered suitable in Alonso does not provide a teaching away from the broader disclosure of using any heterologous signal peptide with the IGF1 polypeptide of Alonso.
Applicant argues on page 8, an ordinary artisan would not have selected the BDNF signal peptide disclosed in Hempstead for use in expression IGF-1 based on the teachings of the references, because Hempstead does not teach or suggest using a heterologous signal peptide to express any protein, much less using a BDNF signal peptide with a non-BDNF protein, and does not teach or suggest that BDNF signal peptide can be used to facilitate transport of a non-BDNF protein into the ER and secretion of the non-BDNF protein. Hempstead teaches that signal peptides are known to facilitate the transport of a protein into ER and secretion of the protein, not that BDNF signal peptide facilitates these functions much better than other signal peptides do.
This is not found persuasive. The instant claims are directed to a product (a composition…) and "the patentability of apparatus or composition claims depends on the claimed structure, not on the use or purpose of that structure." Catalina Mktg. Int'l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801,809 (Fed. Cir. 2002). Note: MPEP 2111.02. All of the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Note: MPEP 2143 KSR International Co. v. Teleflex Inc., 550 US 398, 82 USPQ 2d 1385 (2007).
In addition, most of the claims do not recite any function. Claims 58 and 61 do recite a wherein clause reciting that the quantity of the secreted protein is higher than the quantity of the secreted protein using a signal peptide homologous to the protein. However, the claims do not recite any requirement that the BDNF signal peptide facilitates the functions of transport of a non-BDNF protein into the ER and secretion of the non-BDNF protein much better than other signal peptides do as argued by applicant. Claims 58 and 61 only recite higher secretion compared to a protein using a homologous signal peptide. In addition, it is well settled that "any need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed." KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 420 (2007). As long as some suggestion to combine the elements is provided by the prior art as a whole, the law does not require that they be combined for the reason or advantage contemplated by the inventor. In re Beattie, 974 F.2d 1309, 1312 (Fed. Cir. 1992); In re Kronig, 539 F.2d 1300, 1304 (CCPA 1976). MPEP 2143.01 and 2144 (IV).
The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991)
Applicant argues on page 9, that a skilled artisan would not have been motivated to use a BDNF signal peptide to express any heterologous protein simply because “Hempstead teaches that a heterologous signal peptide can be fused to IGF1 to facilitate transport into the ER and facilitate secretion from cells”, and that this teaching for providing motivation is simply the definition of a signal peptide well known in the art. Applicant argues a skilled artisan would have known that the purpose of signal peptides is to facilitate transport into the ER and facilitate secretion from cells and would not have had any motivation to select the particular signal peptide from BDNF based on this definitional disclosure, and states See, eWEBSTER.
This is not found persuasive, because as responded to above, selection of any signal peptide that is heterologous to the IGF1 of Alonso would have been obvious to try, and amounted to substituting one known signal peptide for another. Regarding applicant’s argument about the teachings of Hempstead merely teaching a definition of a signal peptide well known in the art as not being motivation, this is not found persuasive, because Hempstead supports using the same BDNF signal peptide as recited in the instant claims and pertains to the same definition of a signal peptide and is therefore analogous art.
Applicant argues on page 9 the lack of reasonable expectation of success for combining the teachings because Alonso does not provide any examples that show expression or secretion level of IGF-1 expressed from a construct encoding IGF-1 and a heterologous signal peptide is higher than the expression or secretion level of IGF-1 expressed from a construct encoding IGF-1 and the native IGF-1 signal peptide, and Hempstead does not provide any examples showing the expression or secretion level of a protein expressed from a construct encoding the protein and BDNF signal peptide is higher than that of the protein expressed from a construct encoding the protein and native signal peptide or the protein or a signal peptide from another protein that is not BDNF.
This is not found persuasive. Regarding applicant’s argument about the references not providing examples that show expression or secretion level of IGF-1 expressed from a construct encoding IGF-1 and a heterologous signal peptide that is higher than the expression or secretion level of IGF-1 expressed from a construct encoding IGF-1 and native IGF-1 signal peptide, or that expression or secretion level of a protein expressed from a construct encoding a protein and BDNF signal peptide is higher than that of the protein expressed from a construct encoding the protein and native signal peptide and another protein that is not BDNF, this is not found persuasive because the rejection is made under 103 and does not need to exemplify all embodiments, only suggest. “Disclosed examples and preferred embodiments do not constitute a teaching away from the broader disclosure or non-preferred embodiment.” In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). MPEP 2123. In addition as previously stated, the instant claims are directed to a product (a composition…) and "the patentability of apparatus or composition claims depends on the claimed structure, not on the use or purpose of that structure." Catalina Mktg. Int'l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801,809 (Fed. Cir. 2002). Note: MPEP 2111.02.
Applicant argues that the instant application provides examples showing the secretion level of the protein expressed from the instant claimed recombinant RNA construct in claim 55 is 3.1-6.1 times higher than the secretion level of a protein expressed from a corresponding recombinant RNA construct comprising a sequence encoding a mature protein and native signal peptide of the protein (compare Cpd.1 and Cpd.4 in Figures 17,19,20 and Example 1). Figure 18 shows an exemplary recombinant RNA construct as recited in claim 55 is more potent in inducing secretion of the protein (Cpd.4 in Fig. 18 and Ex: 1) compared to a corresponding recombinant RNA construct that comprises a sequence encoding a protein and a native signal peptide of the protein (e.g., Cpd.1 in Fig. 18 and Example 1). Applicant argues on page 10, that Fig. 17 and 19 show the secretion level of the expressed protein is higher than the secretion level of the same non-BDNF protein expressed from other recombinant RNA constructs comprising a sequence encoding a non-BDNF signal peptide that is heterologous to the non-BDNF protein (compare Cpd.4 with Cpd.2, Cpd.3, Cpd.5, Cpd.6, and Cpd.7 in Figs 17 and 19 and Example 1). Replacing the native signal peptide of the protein with at least 85% identity to the amino acid sequence encoded by SEQ ID NO: 7 or 8 with the signal peptide of insulin or NGF that are described as suitable heterologous signal peptide to be used with another protein in Alonso, does not lead to better secretion of the protein (compare Cpd.1, Cpd.10, and Cpd.13 in Fig. 22 and Example 1). Therefore, applicant argues the present application provides unexpected results of achieving a higher level of secretion of IGF-1 using a construct comprising the BDNF signal peptide and the IGF-1 coding sequence, and is unexpected at least because replacing the native IGF-1 signal peptide with the signal peptide of Insulin or NGF taught by Alonso as suitable heterologous signal peptides does not lead to increased level of IGF-1 secretion and in fact decreases secretion of the IGF-1.
This is not found persuasive. Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. An unexpected property or result must actually be unexpected and of statistical and practical significance. The burden is on the applicant to establish the results are in fact unexpected, unobvious and of statistical and practical significance. See MPEP 716.02. The fundamental requirement is that, “any superior property must be unexpected to be considered as evidence of non-obviousness.” Pfizer, Inc. v. Apotex, Inc. 480 F.3d 1348, 1371 (Fed. Cir. 2007). Applicants have provided no evidence the results are unexpected (i.e. by establishing what the expected effect would be). According to the teachings of Guler-Gane it would be expected that the level of expression of the protein can be modified by replacing the signal peptide and this has shown to be the case in a number of studies, where replacement of the native signal peptides with those from proteins that are known to secrete at high levels can significantly improve secreted levels, and the potential posed by utilizing heterologous signal peptides from highly secreted proteins to improve protein yields is an attractive one (page 2, bottom). Therefore, Guler-Gane suggests using heterologous signal peptides from highly secreted proteins to improve protein yields so this would be an expected effect. The instant specification on pages 119-120 shows results that while Cpd.4 induced higher IGF1 secretion than Cpd.1, Cpd.1 still facilitates cellular exit of IGF1. In addition, page 121 also shows data of the Cpd.1 control to compared other compounds using other heterologous signal peptides, and that while some compounds induced IGF1 secretion higher compared to Cpd.1, all of the signaling peptides used still facilitated cellular exit of the produced IGF1. Therefore, while the BDNF signal peptide may have better results, this does not mean it is an unexpected effect of statistical and practical significance. Determining the optimal signal peptide does not equate to an unexpected effect.
In addition, whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) Note: MPEP 716.02(d).” In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960).
It is noted that the unexpected results for Cpd. 4 cited by applicant are for 100% identity to the exact sequences of SEQ ID NOs: 7 and 8, and which are not part of a larger sequence. In contrast, claims 55,59-61,65-69,73,75-82,83 and 84 only require at least 85% identity to the amino acid sequence encoded by SEQ ID NO: 7 or 8, claim 56 at least 90% identity, claim 64 at least 95% sequence identity, and claim 82 recites comprising an amino acid sequence encoded by SEQ ID NO: 7 or 8 but still could be part of a larger sequence. Therefore, applicant’s unexpected results are not commensurate in scope with the claimed range.
For these reasons, the 103 rejection is maintained.
Claims 65,66 and 73 are rejected under 35 U.S.C. 103 as being unpatentable over Guler-Gane, et al. (PLOS ONE, Vol 11 No 5, 19 May 2016), Alonso et. al. (US 2012/0093775; Published: Apr. 19,2012; Effectively filed: Mar. 26, 2010) and Hempstead et. al. (US 2008/0025978 Al; Published: Jan. 31, 2008; Effectively filed: Jul. 27, 2007) as applied to claim 55 above, and further in view of Jani and Fuchs (Journal of Visualized Experiments, Vol 61, 26 March 2012).
Regarding claims 65-66, Guler-Gane, Hempstead, and Alonso teach all of the elements of the current invention for claim 55 as stated above.
Guler-Gane, Alonso, and Hempstead do not teach that the composition comprises the recombinant RNA construct, wherein the recombinant RNA construct is a recombinant messenger RNA (mRNA) construct, and wherein the recombinant RNA construct further comprises an anti-reverse cap analog (ARCA) and/or an internal ribosome entry site (IRES) at the 5' end.
Jani and Fuchs teach a composition comprising a recombinant RNA construct (page 1, abstract, paragraphs 1 and 2), including a recombinant RNA construct encoding the naturally secreted protein Gaussia luciferase (GLuc) and Cypridina luciferase (CLuc) (pages 1-3, protocol steps 1-5; page 8, Discussion, paragraph 4), and a recombinant RNA that comprises an antireverse cap analog (ARCA) (pages 1-2, protocol steps 1; page 8, Discussion, paragraph 2). Jani and Fuchs teach that recombinant mRNA constructs are useful in applications that require large amounts of high-quality RNA, such as RNA structure and function studies, RNA vaccine development, and transfection and expression experiments (page 1, abstract, paragraphs 1 and 2; pages 7-8, Discussion, paragraphs 1-2). Jani and Fuchs also teach that the 5’ cap is essential for RNA stability and efficient translation, and that use of ARCA yields “functionally active capped RNA suitable for transfection or other applications” (page 1, abstract, paragraph 3). Additionally, use of a composition that comprises ARCA, “ensures incorporation of the cap in the correct orientation” as taught by Jani and Fuchs (page 8, Discussion, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the compositions of Guler-Gane, Alonso and Hempstead to incorporate the teachings of Jani and Fuchs and produce a recombinant mRNA construct that further comprises an anti-reverse cap analog to encode the heterologous signal peptide of BDNF operably linked to the IGF1 protein. One of ordinary skill in the art would have been motivated to do so based on the advantages of using recombinant mRNA constructs and ARCA, as taught by Jani and Fuchs above. Further, as Jani and Fuchs report a composition comprising recombinant RNA constructs, that further comprises ARCA, encoding proteins with signal peptides, there is a reasonable expectation that Jani and Fuchs’ composition could be successfully applied to the expression constructs of Guler-Gane, Alonso and Hempstead, which also encode proteins with signal peptides.
Regarding claim 73, Guler-Gane, Alonso, and Hempstead teach all of the elements of the current invention for claim 55 as stated above.
Guler-Gane, Alonso, and Hempstead do not teach a method of synthesizing the composition of claim 55, wherein the method comprises synthesizing a recombinant RNA construct in vitro.
Jani and Fuchs teach an in vitro transcription method for the synthesis of RNA transcripts (page 1, abstract, paragraphs 1 and 2) and applies this method to the synthesis of mRNA encoding the naturally secreted proteins Gaussia luciferase (GLuc) and Cypridina luciferase (CLuc) (pages 1-3, protocol steps 1-5; page 8, Discussion, paragraph 4). Jani and Fuchs teach that in vitro transcription methods are useful to generate recombinant mRNA constructs for applications that require large amounts of high-quality RNA, such as RNA structure and function studies, RNA vaccine development, and transfection and expression experiments (page 1, abstract, paragraphs 1 and 2; pages 7-8, Discussion, paragraphs 1-2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the compositions of Guler-Gane, Alonso and Hempstead to incorporate the teachings of Jani and Fuchs and use their in vitro method to synthesize a recombinant RNA construct that encodes the BDNF signal peptide operably linked to the IGF1 protein. One of ordinary skill in the art would have been motivated to do so based on the advantages of using in vitro transcription methods, as taught by Jani and Fuchs above. Further, as Jani and Fuchs synthesize recombinant RNAs that encode proteins with signal peptides, and state that, “the method described in this paper can be used to transcribe, cap and transfect any desired mRNA” (page 8, Discussion, paragraph 4), there is a reasonable expectation that Jani and Fuchs’ method could be successfully applied to the expression constructs of Guler-Gane, Alonso and Hempstead.
Response to Arguments
Applicant's arguments filed 09/03/2025 have been fully considered but they are not persuasive.
Applicant argues on page 11 that as claims 65,66 and 73 depend from claim 55, they are not obvious over Guler-Gane, Hempstead, and Alonso and Jani and Fuchs for at least the reasons that claim 55 is not obvious, and because the combination of Guler-Gane, Hempstead, Alonso and Jani and Fuchs does not teach or suggest all of the limitations of claim 55.
This is not found persuasive. No new arguments are made, and the examiner has responded to the arguments pertaining to claim 55 in the response above, and therefore the response provided by the examiner to the rejection of claim 55 also pertains to the rejection of the dependent claims and the rejection is maintained.
Claims 67 and 68 are rejected under 35 U.S.C. 103 as being unpatentable over Guler-Gane, et al. (PLOS ONE, Vol 11 No 5, 19 May 2016), Alonso et. al. (US 2012/0093775; Published: Apr. 19,2012; Effectively filed: Mar. 26, 2010) and Hempstead et. al. (US 2008/0025978 Al; Published: Jan. 31, 2008; Effectively filed: Jul. 27, 2007), as applied to claim 55 above, and further in view of Holtkamp, et al. (Blood, Vol 108 No 13, 15 December 2006).
Regarding claims 67 and 68, Guler-Gane, Hempstead, and Alonso teach all of the elements of the current invention for claim 55 as stated above.
Guler-Gane does not teach that the recombinant RNA construct, wherein the recombinant RNA construct further comprises a polyA tail at the 3’end and that the polyA tail is 120 bp in length.
Holtkamp teaches a recombinant RNA construct encoding eGFP and eGFP variant markers, wherein the recombinant RNA construct further comprises a polyA tail at the 3’end and that the polyA tail is 120 bp in length (page 4010, Figure 1; page 4013, section “Poly(A) tail length has an impact on translational efficiency” and Figure SA-C). Holtkamp teaches that a recombinant RNA construct with a 120 bp polyA tail results in higher protein levels compared to proteins expressed from an RNA construct with a shorter tail, and RNA constructs with longer tails did not significantly affect expression (page 4013, section “Poly(A) tail length has an impact on translational efficiency”). Further, Holtkamp teaches that a 120 bp polyA tail “can be achieved by encoding the poly(A) tract in the template vector rather than attaching it by enzymatic polyadenylation” (page 4015, column 1, paragraph 3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Guler-Gane, Alonso, and Hempstead to incorporate the teachings of Holtkamp and use an RNA construct with a defined and uniform 120 bp polyA tail at the 3’end to encode the BDNF signal peptide operably linked to the IGF1 mature protein. One of ordinary skill in the art would have been motivated to do so based on the advantages of using an RNA construct with a 120 bp polyA tail, as taught by Holtkamp above. Further, as Holtkamp synthesize recombinant RNAs with a defined and uniform 120 bp polyA tail by encoding the polyA tract in the DNA template vector, there is a reasonable expectation that it could be successfully applied to the expression construct of Guler-Gane, which is also a DNA-based vector.
Response to Arguments
Applicant's arguments filed 09/03/2025 have been fully considered but they are not persuasive.
Applicant argues on page 11 that as claims 67 and 68 depend from claim 55, they are not obvious over Guler-Gane, Hempstead, and Alonso and Holtkamp for at least the reasons that claim 55 is not obvious, and because the combination of Guler-Gane, Hempstead, Alonso and Holtkamp does not teach or suggest all of the limitations of claim 55.
This is not found persuasive. No new arguments are made, and the examiner has responded to the arguments pertaining to claim 55 in the response above, and therefore the response provided by the examiner to the rejection of claim 55 also pertains to the rejection of the dependent claims and the rejection is maintained.
Claim 69 is rejected under 35 U.S.C. 103 as being unpatentable over Guler-Gane, et al. (PLOS ONE, Vol 11 No 5, 19 May 2016), Alonso et. al. (US 2012/0093775; Published: Apr. 19,2012; Effectively filed: Mar. 26, 2010) and Hempstead et. al. (US 2008/0025978 Al; Published: Jan. 31, 2008; Effectively filed: Jul. 27, 2007) as applied to claim 55 above, and further in view of Kotaoka et al. (US9314529B2, published 19 April 2016).
Regarding claim 69, Guler-Gane, Hempstead, and Alonso teach all of the elements of the current invention for claim 55 as stated above.
Guler-Gane does not teach a pharmaceutical composition comprising the composition of claim 55 and pharmaceutically acceptable excipient, carrier, or diluent.
Kotaoka teaches a nucleic acid delivery composition (column 31, claim 1), a carrier composition (column 33, claim 4), and a pharmaceutical composition used for nucleic acid therapy, comprising the nucleic acid delivery composition according or the carrier composition (column 36, claims 6 and 8). Kataoka teaches that any nucleic acid can be used with their compositions, and that “examples of nucleic acid include DNA, RNA, naturally-occurring or non-naturally-occurring nucleic acid analogues (such as peptide nucleic acids), altered nucleic acids and modified nucleic acids, and any of these may be used. In addition, the nucleic acid may be a single-stranded nucleic acid or double-stranded nucleic acid, and there are no restrictions on the presence or absence of a protein encoding function or other functions” (column 14, lines 27- 36). Kataoka also teaches that their compositions have low cytotoxicity, and high