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 amendment filed 10/14/2025 is acknowledged. Claim 6 is canceled.
Applicant’s election without traverse of Invention I, Claims 1-12, drawn to an engineered viral particle, and the required species in the reply filed on 6/10/2025 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Claims 13-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 6/10/2025.
Applicant elected the following species:
A specific CD4 ligand: DARPin. Upon further consideration, the examiner hereby withdraws the election of species requirement for group A).
One or more specific viral vectors: claim 2. Upon further consideration, the examiner hereby withdraws the election of species requirement for group B).
Claims 1-5 & 7-12 are under examination on the merits.
Information Disclosure Statement
The Information Disclosure Statements (IDSs) submitted on 7/23/2025, and 11/12/2025 are in compliance with 37 CFR 1.97. Accordingly, the IDSs are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Response to Amendment
Applicant’s arguments, see pp. 1-9, filed 10/14/2025, with respect to objections to the specification and claims, and rejections under 35 U.S.C. §§102 &112(b) have been fully considered and are persuasive. The objections to the specification and claims, and rejections under 35 U.S.C. §§102 &112(b) have been withdrawn.
Applicant's arguments filed 11/12/2025 regarding the rejections under 35 U.S.C. §103 have been fully considered but they are not persuasive. See response below.
New claim objections to claims 5 and 9 are raised below.
Rejections Removed
The following objections and rejections are hereby withdrawn due to Applicant’s amendment filed 11/12/2025:
Objections to the specification.
Objections to claims 2-4, 6, 8-10, and 12.
35 U.S.C. §112(b) rejections of claims 1-12 under.
35 U.S.C. §102(a) rejections of claims 1-2, 5, & 10 as being anticipated by Munch, et al. (Nat Commun. 2015 Feb 10;6:6246. doi: 10.1038/ncomms7246. PMID: 25665714 ); claims 1-2, 4-5 & 10-12 as being anticipated by Jiang et al. (Hum Gene Ther. 1999 Nov 1;10(16):2627-36. doi: 10.1089/10430349950016663. PMID: 10566890); and claims 11-12 as being anticipated by Tao, et al. (Adv Drug Deliv Rev. 2019 May;145:57-72. doi: 10.1016/j.addr.2018.06.025. Epub 2018 Jul 6. PMID: 2998180).
New Objections
Claim 5 is objected to because of the following informalities: claim 5 contains a typographical mistake on line 2, where it recites “HIV envelop protein” rather than “HIV envelope protein”. Appropriate correction is required.
Claim 9 is objected to because of the following informalities: claim 9 recites “SEQ ID No. 1” and “SEQ ID No. 2” on lines 2, rather than the proper form “SEQ ID NO: 1” and “SEQ ID NO: 2”. Appropriate correction is required.
Maintained Rejections
Claim Rejections - 35 USC § 103
(New Rejection Necessitated by Amendments- Claims 11-12 Added) Claims 1-5, 7, 8 and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Tao et al. (Adv Drug Deliv Rev. 2019 May;145:57-72. doi: 10.1016/j.addr.2018.06.025. Epub 2018 Jul 6. PMID: 2998180; hereinafter referred to as “Tao”) and in further view of Jiang et al. (Hum Gene Ther. 1999 Nov 1;10(16):2627-36. doi: 10.1089/10430349950016663. PMID: 10566890; hereinafter referred to as “Jiang”). Claims 11-12 are added. The rejection of claim 6 is withdrawn due to cancellation of the claim.
The claimed invention encompasses an engineered viral particle, comprising: at least one viral vector, and at least one CD4 ligand, wherein the at least one CD4 ligand is displayed on the surface of the at least one viral vector, and wherein the CD4 ligand is linked through a linker to at least one protein selected from the group consisting of: Hoc and Soc, as recited in claim 1. In a specific embodiment, the at least one viral vector is selected from the group consisting of: Lambda phage, Bacillus phage Phi29, Escherichia coli phages T2, T3, T4 and T7, Enterobacteriaphage P22, phage SPP1, Filamentous phages, Herpes viruses, adenovirus, adeno-associated viruses (AAV), retroviruses, and lentiviruses, as recited in claim 2. In another embodiment, the Filamentous phages are selected from the group consisting of: M13, fd, and F1, as recited in claim 3. In a different embodiment, the CD4 ligand is an HIV component that interacts with CD4, as recited in claim 4. Alternatively, the CD4 ligand is CD4-binding DARPin (Designed Ankyrin Repeat Proteins) or HIV envelop protein, as recited in claim 5. In a more specific embodiment, the linker is a sequence consisting of 2-25 amino acids, as recited in claim 7. In a different embodiment, the linker projects the CD4 ligand away at least 170 Å from the capsid wall of the viral vector, as recited in claim 8.
In a different embodiment, the engineered viral particle further comprises at least one nucleic acid packed in the viral vector, as recited in claim 10.
Another embodiment of the claimed invention is an engineered viral particle comprising: at least one viral vector; and at least one HIV-1 envelope protein, wherein the at least one HIV-1 envelope protein is displayed on the surface of the at least one viral vector, and wherein the HIV-1 envelope protein is linked through a linker to at least one protein selected from the group consisting of: Hoc and Soc, as recited in claim 11. In a more specific embodiment, the HIV-1 envelope protein is selected from the group consisting of: gp140, gp120, and a fragment of the envelope protein, as recited in claim 12.
The Prior Art
Tao teaches assembly of antigens into virus-like particles for presentation of immunogenic epitopes in a native context (Abstract). Tao further discloses that bacteriophages such as phage T4 provide excellent platforms to generate nanoparticle vaccines, due to the T4 capsid containing two non-essential outer proteins Soc and Hoc, which allow high density array of antigen epitopes in the form of peptides, domains, full-length proteins, or even multi-subunit complexes (Abstract). For instance, the T4 capsid has 870 copies of Soc and 155 copies of Hoc on the surface, which enabled up to 860 copies of the gp41 envelope protein of HIV-1 to be displayed on T4 capsid through Soc, leading to a density 60-120 times higher than that present on the HIV virion (p. 60, col., 2, para. 2). Tao discloses that a number of HIV-1 antigens have been displayed on Soc on T4 nanoparticle vaccine candidates, including gp41, v3 loop of gp120, p24, and Nef (Table 1). Further, the particles are capable of co-delivery of DNAs or targeting molecules (Abstract; p. 61, col. 1, para. 4). Tao also discloses that filamentous phages including M13, fd, and f1 may be used to develop VLP vaccines, having the advantages including different sizes, topology, and/or outer capsid proteins (pp. 67-68, bridging para.). Tao also teaches that T4 Hoc protein projects away ~170 Å away from the capsid wall (p. 62, col. 2, para. 2), and that Hoc fiber can be used to target the VLP to specific cells by attaching a ligand to the tip of the fiber (p. 65, cols. 1-2, bridging para.; Fig. 5; Table 1). However, Tao does not disclose an engineered viral particle comprising at least one CD4 ligand.
Jiang teaches genetically engineered Spleen Necrosis Virus (SNV)-derived retroviral vector particles that display the complete HIV-1 gp120 surface unit, fused to a short peptide spacer coding region (Gly4Ser)3, linking it to the SNV TM-coding region (Abstract). Particles harvested from stable packaging lines infected CD4+ human hematopoietic cells with titers exceeding 105 CFU/ml supernatant tissue culture medium, whereas titers in other, CD4- cell lines expressing other coreceptors of HIV-1 were 100-fold lower than titers obtained from CD4+ cells (Abstract; Table 1). Jiang further teaches that infection through CD4 is more efficient than infection through a coreceptor (p. 2633, para. 2; Table 1). Jiang further discloses that the SNV-derived vectors encode β-galactosidase (lacZ) gene (p. 2628, col. 2, para. 2; Fig. 1; Table 1).
It would have been obvious to one of ordinary skill in the art to modify the phage vectors taught by Tao to express linked HIV-1 gp120. Tao teaches that a number of HIV-1 antigens have been displayed on Soc on T4 nanoparticle vaccine candidates, including gp41, v3 loop of gp120, p24, and Nef. Jiang teaches viral particles that display the complete HIV-1 gp120 surface unit, fused to a short peptide spacer coding region (Gly4Ser)3. Jiang further indicates that HIV-1 gp120 surface display binds to CD4 on cells, and thus is a CD4 ligand. One of ordinary skill in the art would have been motivated to deliver HIV-1 gp120 as an immunogen. One of ordinary skill in the art would have had a reasonable expectation of success because the prior art demonstrates effective display of foreign proteins on the phage particles, as well as construction of viral vectors comprising HIV-1 gp120 fused to native viral structural proteins by a linker. Therefore, claims 1-5, 7, 8, and 10-12 were prima facie obvious before the priority date of the instant application.
Applicant’s arguments have been carefully considered but are found not to be persuasive.
Applicant presents the following arguments:
Tao and Jiang fail to disclose or suggest any of the exemplary features recited in the amended independent Claim 1. Tao is directed towards the potential of T4 bacteriophages in developing VLP platforms to design multivalent vaccines against complex and emerging pathogens, by displaying immunogens on Hoc and Soc proteins, which are non-essential outer proteins present on the T4 capsid, On the other hand, Jiang teaches the use of SNV-derived retroviral vectors for displaying the HIV-1 gp120 protein on the surface of the vector. There is no teaching or motivation for a person of ordinary skill in the art to refer to Jiang in the first place. The bacteriophage T4 in Tao and SNV in Jiang are two completely different viruses based on their structure and function. Jiang uses the whole SNV vector as a targeting device to deliver the displayed gp120 to specific human cells (hematopoietic stem cells). In the claimed invention, a displayed targeting molecule (CD4DARPin) was used to deliver the vector (and its payload) to specific human cells (T cells). It is submitted that a skilled person referring to the disclosure of Jiang would not substitute the SNV vector with T4 vector since the T4 vector as such lacks any targeting function. Thus, there is no motivation for a person of ordinary skill in the art to replace the SNV in Jiang with the T4 phage of Tao, let alone make such a selection to prepare an engineered viral particle as claimed in the instant Application.
There is no teaching or motivation in Tao to use a linker with Hoc and Soc proteins in order to display a ligand on the surface of the T4 capsid. FIG. 5 of Tao clearly shows that the antigen (or a ligand) is linked directly to the Soc/Hoc protein for display on the T4 capsid; there is no linker involved. In the instant Application, since the T4 is being targeted to specific human cells (T cells), using a flexible linker enhances the reach of the targeting molecule and creates flexibility to scan the environment for finding its binding partner, which is not suggested in Tao.
Jiang describes the use of a short peptide spacer coding region for connecting the SNV TM (tramsmembrane) region, since the spacer helps in achieving flexibility and enables correct folding of both peptides. This is also required since SNV is an enveloped virus and depends on membrane fusion with the host cell for its genetic material to enter the host cell. However, there is no such requirement in the claimed invention, as in the claimed invention, the CD4 ligand binds to surface proteins of the viral vector through a linker which enables efficient display of the CD4 ligand on the surface of the viral vector.
In summary, Tao does not disclose a CD4 ligand (as acknowledged by the Examiner) and while Jiang discloses HIV-1 gp120 bound to a short peptide spacer coding region, which reads on the CD4 ligand and linker of the claimed invention, there is no teaching or motivation in Jiang to use T4 as a vector for displaying HIV-1 gp120. Thus, for a person of ordinary skill in the art to arrive at the engineered viral particle of the claimed invention, the person would have to make multiple selections from both Tao and Jiang, which is not possible without hindsight knowledge of the claimed invention. Therefore, the claimed invention is non-obvious over the cited prior art.
Additionally, to establish a prima facie case of obviousness of a claimed invention, all the claim limitations must be taught or suggested by the prior art. The present office action fails to show all elements of the claimed invention. Therefore, it is respectfully submitted that neither Tao nor Jiang, taken alone or in any proper combination, discloses or suggests the subject matter as recited in amended independent claim 1. The remaining dependent Claims 2-5, 7-8, and 10 depend from independent Claim 1 and is patentable over the cited reference for at least the same reasons as set forth above with respect to independent claim 1 as well as the additional limitations recited therein.
Applicant’s arguments are not persuasive because:
While it is true that the viruses disclosed by Tao and Jiang are different, that does not mean that the teachings from Tao and Jiang are not relevant to one another. Both Tao and Jiang contemplate fusing HIV proteins to foreign heterologous viral vectors for certain purposes. In each reference, HIV proteins are genetically manipulated and anchored onto the surface of a different virus.
The focus is engineering proteins for display on viral vectors. Notably, the claimed invention is broad, is a product, and it is relevant to consider what one of ordinary skill in the art would be looking for regarding information in that field. The HIV glycoproteins are well studied, and making recombinant fusion proteins in this field of endeavor is well known and common prior to the priority date (7/13/2021).
Applicant’s arguments are not convincing because the breadth of the claims are broad, and the teaching of Tao enables one of ordinary skill in the art to take the example, and, in theory, attach any protein that can physically be attached and presented on the surface of T4. Reading the teachings of Tao, it is clear that they contemplate presenting HIV proteins on the surface of a virus, such as phage. The phage are engineered such that gp41 is attached to Soc. Tao points to particular HIV proteins that are of interest, and in a very predictable way, linked it to the surface of Soc. It would be obvious to one of ordinary skill in the art that other HIV proteins, such as gp120, could be considered. One of ordinary skill in the art would consider what else is known about affixing HIV proteins on the surface of a virus, and find Jiang. There is a reasonable expectation of success by using the linker of Jiang, and how they created a fusion protein by gp120 and SNV.
Applicant’s claims encompass a product, so we must consider what the product is defined by. The only deficiency of Tao is that it does not provide a linker for fusing gp120 to Soc. This is an obviousness type rejection and Tao provides teachings on why focusing on HIV is important, and ways to engineer the antigens. Jiang provides the fusion protein of gp120 with a linker. Each reference is focused on viral vector presentation, and there is a reasonable expectation of success because they both achieved that. The reason for doing so might not be identical, but is within the ability of one of ordinary skill in the art to adapt the teachings of each reference to fit their particular needs.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
(New Rejection Necessitated by Amendments) Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Tao (supra) and Jiang (supra), as applied to claims 1-5, 7-8 and 10-12 above, and in further view of Rosmalen et al. (Biochemistry. 2017 Dec 19;56(50):6565-6574. doi: 10.1021/acs.biochem.7b00902. Epub 2017 Dec 7. PMID: 29168376; hereinafter referred to as “Rosmalen”).
In another embodiment of the claimed invention, the linker is at least one selected from the group consisting of: SEQ ID NO: 1 and SEQ ID NO: 2, as recited in claim 9.
The Prior Art
The teachings of Tao and Jiang are described above. However, they do not teach a linker selected from the group consisting of: SEQ ID NO: 1 and SEQ ID NO: 2.
Rosmalen teaches use of Glycine-serine linkers to allow rational design of multidomain proteins (Rosmalen, generally). Rosmalen tested fusion proteins constructed with linkers that contain between one and nine GGSGGS repeats (p. 6568, col. 1, para. 2). Rosmalen further teaches that flexible linkers consisting of repeats of serine and glycine are widely used in the construction of multidomain proteins (p.6570, col. 2, para. 2), and there is an observed increase in linker stiffness with reduced glycine content (Abstract). SEQ ID NO: 2 is GGSGGSGGSGGS, or two repeats of GGSGGS sequence.
It would have been obvious to one of ordinary skill in the art to modify the phage vectors taught by Tao to express linked HIV-1 gp120, with SEQ ID NO: 2 as a linker. One of ordinary skill in the art would have been motivated to deliver HIV-1 gp120 as an immunogen. One of ordinary skill in the art would have had a reasonable expectation of success because the prior art demonstrates effective display of foreign proteins on the phage particles, as well as construction of viral vectors comprising HIV-1 gp120 fused to native viral structural proteins by a linker. Therefore, claim 9 was prima facie obvious before the priority date of the instant application.
Applicant’s arguments have been carefully considered but are found not to be persuasive.
Applicant presents the following arguments:
Claim 9, as currently amended, depends on amended independent Claim 1, which recites a specific combination of features that distinguishes the invention from Tao and Jiang in different ways, as outlined above. At the very least, Tao and Jiang fail to disclose or suggest any of these exemplary features recited in amended Independent Claim 1. A skilled person in the art would have to make multiple selections from both Tao and Jiang to arrive at the claimed invention, which cannot be possible without hindsight knowledge of the claimed invention. Rosmalen describes linkers with different glycine content that can be used for designing multidomain proteins. There is no teaching or disclosure in Rosmalen regarding an engineered viral particle as claimed in the instant Application. In fact, Rosmalen fails to disclose anything with respect to SEQ ID NO: 1. While glycine-rich linker sequences similar to SEQ ID NO: 2 have been disclosed in Rosmalen, p. 6572, left column of Rosmalen suggests that polyserine linkers are more effective and enable efficient interactions over a broad range of linker lengths. Thus, a skilled person would not have been able to arrive at the subject matter recited in Claim 9.
Applicant’s arguments are not persuasive because:
Contrary to Applicant’s argument, the Examiner has concluded that Tao in view of Jiang render obvious claim 1. The mere fact that Rosmalen suggests polyserine linkers are more effective over a broad range of linker lengths would not necessarily dissuade one of ordinary skill in the art from using glycine-rich linker sequences similar or SEQ ID NO: 2.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JEFFREY MARK SIFFORD/Examiner, Art Unit 1671 /BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671