Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Formal Matters
2. Applicant should submit one claim set in response to this Office Action, if needed. Please do not submit the original claim set with the amended claims, if needed, in the response.
Status of Claims
3. Applicant's preliminary amendment of the instant application, which was originally submitted on 01/06/2023 and later amended on the same day, then 06/30/2023, is acknowledged by the Examiner. The cancellation of claims 7 – 9 and 21 pursuant to the amendment on 01/06/2023 and claims 22 and 23 pursuant to the amendment on 06/30/2023 is acknowledged. Claims 1 – 6, 10 – 20, 24, and 25 were subsequently restricted in the Office Action mailed on 12/03/2025.
Election/Restrictions
4. Applicant's election with traverse of Group III for claims 10 – 14 in the reply filed on 01/26/2026 is acknowledged. The traversal is on the ground(s) that there is no undue burden on the Examiner to consider all the claims in a single application. This is not found persuasive because this is a National Stage Entry application, which is held to a different legal standard than . National Stage Entry applications follow the rules set forth in 35 U.S.C. 371, i.e., unity of invention, whereas domestic applications follow 35 U.S.C. 111, i.e., undue search burden. See MPEP § 803 and MPEP § 1893.03(d).
Applicant is applying an incorrect legal standard in their argument, and so it is not persuasive. Thus, while the instant claims have a unifying technical feature, it has previously been taught and is not a special technical feature over the art for the reasons set forth in the restriction (see Office Action mailed on 12/03/2025). In turn, the requirement is still deemed proper and is therefore made FINAL.
Claims 1 – 6, 15 – 20, 24, and 25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 10 – 14 are pending in this application and under examination. Applicant timely traversed the restriction (election) requirement in the reply filed on 01/26/2026.
Priority
5. The instant application is a National Stage Entry of International Patent Application No. PCT/CN2021/104793 filed on 07/06/2021, and also claims priority to China Patent Application No. 202010642753.8 filed on 07/06/2020; China Patent Application No. 202010642754.2 filed on 07/06/2020; China Patent Application No. 202010642744.9 filed on 07/06/2020; China Patent Application No. 202010642755.7 filed on 07/06/2020; and China Patent Application No. 202010642745.3 filed on 07/06/2020. It is noted that United States Patent Application No. 18014647, which is a National Stage Entry of International Patent Application No. PCT/CN2021/104641, also claims priority to China Patent Application No. 202010642745.3 filed on 07/06/2020 as well as China Patent Application No. 202010945335.6 filed on 09/10/2020.
It is noted, however, that Applicant has not filed a certified copy of these applications that complies with 37 CFR 1.55. An English language translation of a non-English language foreign application is required (i) when the application is involved in an interference or derivation proceeding; (ii) when necessary to overcome the date of a reference relied upon by the Examiner; or (iii) when specifically required by the Examiner. Should Applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e). Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
6. The information disclosure statements (IDS) submitted on 01/06/2023 has been considered by the Examiner. The International Search Report and Written Opinion of the International Searching Authority have been placed in the Application File, but are not listed on the IDS. Thus, the IDS fails to comply with 37 CFR 1.98(a)(1), which requires the following: (1) a list of all patents, publications, applications, or other information submitted for consideration by the Office; (2) U.S. patents and U.S. patent application publications listed in a section separately from citations of other documents; (3) the application number of the application in which the information disclosure statement is being submitted on each page of the list; (4) a column that provides a blank space next to each document to be considered, for the Examiner’s initials; and (5) a heading that clearly indicates that the list is an information disclosure statement. All references on the IDS have been considered, however.
Notably, 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." Thus, unless the references have been cited by the Examiner on form PTO-892, they have not been considered.
Specification
7. The disclosure is objected to because of the following informalities:
There is a typographical error on page 3. The phrase should read “adjuvants simultaneously” and not “adjuventssimultaniouly” as presently written;
There is a typographical error on page 4. The word should read “deleted” and not “delelted” as presently written;
There is a typographical error on page 5. The phrase should read “some inventors” and not “someinventgors” as presently written;
There is a typographical error on page 5. The word should read “increased” and not “incrased” as presently written;
There is a typographical error on page 5. The phrase should read “our further” and not “outfuther” as presently written;
There is a typographical error on page 6. The word should read “further” and not futher” as presently written;
There is a grammatical error on page 6. The phrase “…with replication, that is need to knock out…”. The phrase should be amended to read “… with replication, there is a need to knock out…”;
There is a typographical error on pages 7, 8, 11, 19, 22, 52 – 54, 64, 65, 75, 76, and potentially others. The word should read “ubiquitin” and not “ubiqutin” as presently written;
There is a typographical error on page 31. The phrase should read “[T]haw a” and not “[T]hawa” as presently written;
All SEQ ID NOs should be listed as “SEQ ID NO: X” and not “Seq ID No. X” as presently written on pages 7 – 9 and 36;
There is a typographical error on page 92. The example is listed as 12.3, but falls under example 49. The number should be “49.3”.
Appropriate correction is required.
8. The use of the terms ATCC® on page 26; Phusion™ on pages 28 and 32; TranscriptAid™ on pages 28 and 33; Axygen™ on pages 29, 30, 34, 37 – 40, 42, 52 – 54, 64, 65, 67, 73, 83, and 84; GeneArt™ on page 31; Gene Jet™ on page 33; and possibly others in the specification, which are trade names or a marks 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 they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, ℠, or ® following the terms. 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. Applicant is required to properly annotate all trade names and/or marks that are present in the specification.
9. The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which Applicant may become aware in the specification. There are numerous typographical errors distributed throughout the specification that Applicant should correct.
Drawings
10. The drawings are objected to because there are random text boxes that read “cell”, “CK”, and “test” on top of the data in figure 60. There are also numerous figures not in numerical order. This includes figures 3 – 5, 24, 25, 34 – 36, 67, 68, 80 – 85, 107, 108, 133, and 134.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the Examiner, the Applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
11. Claims 12 – 14 are objected to because of the following informalities:
Claim 12, lines 1 and 2 recite the phrase “wherein the four antigen genes are each any one of the following five groups of antigen genes”. This is grammatically incorrect. It is recommended that the phrase read “wherein one group is selected from the following five groups of four antigen genes”;
Claim 13, lines 5 and 6 recite the phrase “…is obtain by adding the molecular adjuvant ubiquitin on the CP129R, the CP120Rubiqutin and the MGF5L6L are express in…”. This is grammatically incorrect. It is recommended that the phrase read “…is obtained by adding the molecular adjuvant ubiquitin on the CP129R, wherein the CP129Rubiquitin and the MGF5L6L are expressed in…”;
Claim 13, lines 10 and 11 recite the phrase “…is obtain by adding the molecular adjuvant ubiquitin to L8L, I73Rhbsag is obtain by adding the molecular adjuvant hbsag to I73R, L8Lubiqutin…”. This is grammatically incorrect. It is recommended that the phrase read “…is obtained by adding the molecular adjuvant ubiquitin to L8L, I73Rhbsag is obtained by adding the molecular adjuvant hbsag to I73R, wherein L8Lubiqutin…”;
Claim 13, lines 15 and 16 recite the phrase “…is obtain by adding the molecular adjuvant ubiquitin on the K205R, the EP402R and the EP135R are express in…”. This is grammatically incorrect. It is recommended that the phrase read “…is obtained by adding the molecular adjuvant ubiquitin on the K205R, wherein the EP402R and the EP135R are expressed in…”;
There is a typographical error in claim 13, line 14. The word “gene” should be plural, i.e., “genes”;
There is a typographical error in claim 13, line 18. The phrase “antigen genes is for” should read “antigen genes is formed”;
There is a typographical error in claims 12 – 14. All iterations of the word “ubiqutin” should read “ubiquitin”;
There is a typographical error in claim 14. The phrase “MGF110-4L, pAd5LCL3-CP129Rubiquitin-MGF5L6L-CP312R-MGF110-4L” should read “MGF110-4L, and pAd5LCL3-CP129Rubiquitin-MGF5L6L-CP312R-MGF110-4L”;
Ubiquitin is drawn to SEQ ID NOs: 15, 21, and 31 in claim 14. The sequences represented by SEQ ID NOs: 15, 21, and 31 are identical. The claim should be simplified as to not have duplicate embodiments;
All SEQ ID NOs in claim 14 should be listed as “SEQ ID NO: X” and not “Seq ID NO. X” as presently written.
Recommended amendments are underlined. Appropriate correction is required.
Claim Rejections - 35 USC § 112
35 USC § 112(b)
12. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION. — The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the Applicant regards as his invention.
13. Claims 12 – 14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the Applicant), regards as the invention.
14. Claims 12 – 14 are vague and unclear, which renders the claim indefinite. Line 2 of claim 12 recites “five groups of antigen genes: a first group: P72, B602L, P30, and P54”. Moreover, lines 2 – 4 of claim 13 recite “P72 and B602L are expressed in the E1 region and P30 and P54 are expressed in the E4 region…in which four antigen genes are co-expressed”. Lines 1 and 2 of claim 14 recite “P72, B602L, P30, and P54…have nucleotide sequences shown by SEQ ID NOs:…”. The instant specification discloses that of these four, only B602L is a gene, which encodes for the PB602L protein (page 3). P30 and P54 are both proteins that are encoded by the CP204L and E183L genes, respectively (page 3). It is also recited that P72 is a protein, but the specific gene that encodes for it is not discussed (page 3). The same is true for P34 and pp62 recited in the fifth group, wherein the specific gene that encodes for it is not disclosed. A gene is not a protein, but rather a nucleotide sequence that encodes for a protein. Moreover, it is stated that ubiquitin, which is a protein, has a nucleotide sequence. Thus, the claim is rendered indefinite. In the interest of compact prosecution and in view of the instant specification, it will be inferred that P72, P30, and P54 are encoded by the disclosed nucleotide sequences, i.e., SEQ ID NOs: 1, 3, and 4, respectively. However, an appropriate amendment is required.
15. Claim 14 refers to sequences that are set forth in tables of the specification. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for Applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted). See MPEP § 608.01(m) and 2173.05(s). In the interest of compact prosecution, it is understood that the SEQ ID NOs listed are correctly drawn to disclosed materials in the instant disclosure. However, “a sequence table” does not need to be the instant sequence listing, and so an appropriate amendment is required.
16. Claim 14 is vague and unclear, which renders the claim indefinite. Lines 5 – 8 recite “CP129R, ubiquitin, MGF5L6L, CP312R, MGFI 10-4L, pAd5LCL3-CP129Rubiqutin-MGF5L6L-CP312R-MGF110-4L respectively have nucleotide sequences shown in Seq ID NO.14, Seq ID NO.15, Seq ID NO.16, Seq ID NO.17, Seq ID NO.18 and Seq ID NO.19”. The incorrect placement of the adverb “respectively” in the middle of the list as opposed to the end of the list results in ambiguity. Similar iterations occur in lines 9 – 19 for the third – fifth groups. It is unclear which SEQ ID NOs are respective to the listed items. The presence of multiple very different interpretations of the same claim language renders the claim indefinite. It is recommended that the limitation be amended to read “CP129R, ubiquitin, MGF5L6L, CP312R, MGFI 10-4L, and pAd5LCL3-CP129Rubiqutin-MGF5L6L-CP312R-MGF110-4L have nucleotide sequences shown in SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18 and SEQ ID NO: 19, respectively,”. Similar amendments are encouraged in lines 9 – 19 for the other groups.
Additionally, lines 6, 10, 14, 17, and 18 recite “have nucleotide sequences shown in SEQ ID NO: X” wherein X is the different sequence number. It is unclear if the respective antigen genes could be the full length of SEQ ID NO or just a partial sequence, i.e., a fragment, thereof. The presence of multiple very different interpretations of the same claim language renders the claim indefinite. It is recommended that the limitation be amended to read “are encoded by SEQ ID NO: X” or a similar iteration.
Moreover, SEQ ID NO: 36 is drawn to both P34 and pp62 in lines 17 and 18 of the claim. It is unclear how SEQ ID NO: 36 is encoding for both P34 and pp62 when P34 and pp62 are two different antigens. The presence of multiple very different interpretations of the same claim language renders the claim indefinite. It is inferred that this is a typographical error. It is recommended that the limitation be amended to “P34, pp62…SEQ ID NO: 35, SEQ ID NO: 36”.
In the interest of compact prosecution, all of the suggested amendments will be employed for other rejections. However, an appropriate amendment is required.
17. It is noted that any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to this Office Action. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejection(s) and art may be applied in a subsequent Office Action.
35 USC § 112(a)
18. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre–AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
35 USC § 112(a) – Written Description
19. Claims 10 and 11 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre–AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre–AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
"The purpose of [the written description requirement] is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification"); LizardTech Inc. v. Earth Resource Mapping Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724, 1732 (Fed. Cir. 2005). This requirement is separate and distinct from the enablement requirement. To satisfy the written description requirement for a claimed genus, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention at the time of filing. See In re Reiffin v. Microsoft Corp., 214 F.3d 1342, 1345, 54 USPQ2d 1915, 1917 (Fed. Cir. 2000). “Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement.” See In re Enzo Biochem, Inc. v. Gen–Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002). See also MPEP § 2163.
The written description requirement may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicant was in possession of the claimed genus. See In re University of California v. Eli Lilly & Co., 119 F.3d 1559, 1566, 43 USPQ2d 1398, 1404 (Fed. Cir. 1997); and Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021).
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, the Applicant must describe a sufficient variety of species to reflect the variation within the genus. See In re AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See In re Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." See In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
The Federal Circuit has clarified the application of the written description requirement to inventions in the field of biotechnology. The Court stated that a written description of an invention requires a precise definition, one that defines the structural features of the chemical genus that distinguishes it from other chemical structures. A definition by function does not suffice to define the genus because it is only an indication of what the genus does, rather than what it is. This is because functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Further, the Court held that to adequately describe a claimed genus, an Applicant must describe a representative number of species of the claimed genus, and that one of skill in the art should be able to “visualize or recognize the identity of the members of the genus.” The description needed to satisfy the written description varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology. See In re University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997); In re AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014); In re Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 94 USPQ2d 1161 (Fed. Cir. 2010); and In re Capon v. Eshhar, 418 F.3d at 1357, 76 USPQ2d at 1084.
Claims 10 and 11 are drawn to a vaccine that is obtained by constructing a recombinant adenovirus vector co-expressing four antigen genes of the African swine fever virus. At a minimum, claims 10 and 11 are generic and encompass a vaccine comprised of any four antigen genes, and their associated proteins, that elicit a neutralizing antibody response against ASFV. No specific antigens are recited. The claims encompass any vaccine with four antigen genes, wherein the instant specification discloses that there are more than 160 antigen genes of ASFV in total (page 3). This corresponds to a massive genus of 1604 = 655,360,000 possible combinations for the vaccine. Moreover, the vaccine must elicit neutralizing antibodies in the subject, which would be uncommon with just any random combination of antigen genes. In general, this creates an enormous breadth of vaccines that Applicant does not provide adequate written description for the claimed genus.
When there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a “representative number” of species. The claims are drawn to several genera that are comprised of a large magnitude of vaccines with different combinations of antigen genes, yet, the specification has only adequately described, and successfully reduced to practice, five groups encompassing four different antigen genes per group, wherein one of the groups include P72, B602L, P30, and P54. In the instant specification, it is taught that P30 is one of the most antigenic ASFV proteins can induce host cells to produce neutralizing antibodies that inhibit intracellular internalization (pages 2 and 3). It is further taught that P54 has virus neutralization abilities, P72 is one of the main detected antigens of ASFV, and PB602L stimulates the production of high-level antibodies (page 3). For the other four groups, the four antigens per group were selected from a list of antigen genes with stronger immune effect, then grouped according to the size of the gene fragment and protein structure so they could be co-expressed completely and independently in the designed vector (page 3). This is not representative of the extremely large genus of antigen genes, and their associated proteins, claimed. One of ordinary skill in the art cannot conclude that Applicant was in possession of the innumerable combinations of antigenic genes encompassed by the disclosed genera. Absent the five different disclosed groups, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, each individual sequence utilized. Thus, it is clear that the breadth of the recited genera in the claims far overreaches the Applicant’s contribution.
In the absence of a representative number of examples, the specification must at least describe the structural features that are required for the claim function. In the instant case, the specification should explain how expression of the vector elicits an effective immune response in a patient. However, the specification fails to describe any substantive structural limitations as to establish a structure–function relationship with respect to an immune response against ASFV. At best, the specification contemplates the use of BLAST to identify functional homologs based on sequence homology. However, this is not sufficient to describe members of the claimed genus because such methods access online databases that are continually being updated as sequencing technology improves. As a result, they are not a static source of information. Therefore, one having ordinary skill in the art would readily appreciate that relying on a non–patent source that is continuously subject to change as a means to identify members of the claimed genus does not sufficiently meet the written description requirement.
The art teaches that protein chemistry is an extremely unpredictable area of biotechnology, wherein even a single substitution can change the biological property of a peptide, wherein some combinations of ASFV antigen genes result in unfavorable immune responses. For example, Burgess, W. H., et. al., (Possible dissociation of the heparin–binding and mitogenic activities of heparin–binding (acidic fibroblast) growth factor–1 from its receptor–binding activities by site–directed mutagenesis of a single lysine residue. The Journal of cell biology, 111(5 Pt 1), 2129–2138; Published 11/1990), hereby Burgess, teaches that replacement of a single lysine residue by a glutamic acid residue can lead to substantial loss of receptor binding and biological activity of a protein (page 2129; abstract). Moreover, Friedberg, I., (Automated protein function prediction––the genomic challenge. Briefings in bioinformatics, 7(3), 225–242; Published 01/25/2006), hereby Friedberg, teaches that homology–based transfer is not reliable for functional annotation even with high alignment percentages (page 227, second column). Friedberg also teaches that identification of functionally significant sub–regions is critical to functional annotation, and that often addition, deletion, or re–shuffling of domains can lead to errors in annotation (page 227, second column; page 228, first paragraph). Furthermore, Friedberg teaches that as databased and, thus, diversity of sequences, get larger, sequence–based tools are not sensitive enough to identify functional protein similarity (page 228, first full paragraph). Thornton, J., (Structural genomics takes off. Trends in biochemical sciences, 26(2), 88–89; Published 02/01/2001), hereby Thornton, teaches that the same protein structure is often seen in apparently different homologous families with different functions. Thornton further describes examples of little correlation between specific binding function and overall protein structure (page 992, right column, lines 2 – 10). Furthermore, Goatley, L. C., et. al., (A Pool of Eight Virally Vectored African Swine Fever Antigens Protect Pigs Against Fatal Disease. Vaccines, 8(2), 234; Published 05/18/2020), hereby Goatley, teaches that a previous screening of 40 ASFV genes for immunogenicity led to an immunization regime that did not protect animals after challenge (page 1, abstract). It is further taught by Goatley that certain antigens, or combinations of antigens, can induce enhanced disease in swine (page 2, second paragraph). Thus, when taken with the teachings of Burgess, Friedberg, Thornton, and Goatley one having ordinary skill in the art would readily appreciate that sequence homology alone cannot serve as the basis to describe members of the genus that have the recited function and that different combinations of antigen genes would be a result effective parameter requiring optimization wherein even a single substitution within the antigen gene could change the effectiveness of the vaccine.
In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function and that any combination of the ASFV antigens will not inherently provide protect immunization responses. In other words, a single mutation in the antigen protein, as encoded by the antigen gene, could result in hindered function, wherein some combinations are known to cause vaccine-induced enhanced disease (Goatley; page 2, second paragraph). Thus, while Applicant has described a species within the genus recited, and the art may provide more, each genus is very large and would encompass peptide structures that cannot be visualized from the prior art or instant disclosure. One having ordinary skill in the art cannot determine the structures encompassed by the claimed genera. Thus, the described species cannot be considered representative of the entire recited genus.
Overall, the claims as currently written are not adequately described and one of ordinary skill in that art would readily appreciate that Applicant was not in possession of the claimed genera at the time of filing. At present, it is recommended that the claims remove all recitations of “vaccine” and amend it to “immunogenic composition” or “therapeutic composition” or provide evidence of a neutralizing antibody response.
35 USC § 112(a) – Enablement
20. Claims 10 – 14 are rejected under 35 U.S.C. § 112, first paragraph, because the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention, because the specification does not provide evidence that the claimed biological materials are (1) known and readily available to the public; (2) reproducible from the written description.
Acknowledgement is made with regard to the deposit information provided on pages 4 and 5 of the instant specification. However, the deposit information is deficient and, thus, it is unclear if the 293TD37 cell line, which produces a vector having the identity of pcDNA3.1+(hyg)-ORF6-IRES-DBP, is known and publicly available, or can be reproducibly isolated without undue experimentation. It is apparent that the claimed cell line, named as 293TD37, deposited in the China Center for Type Culture Collection (CCTCC) with preservation number CCTCC NO: C201996 is required to practice the claimed invention since it is a recited limitation. As a required element, it must be known and readily available to the public or obtained by a repeatable method set forth in the specification. Therefore, a suitable deposit for patent purposes is suggested. Without a publicly available deposit of the above cell line, one of ordinary skill in the art could not be assured of the ability to practice the invention as claimed.
Exact replication of: (1) the claimed cell line; (2) a cell line which produces the chemically and functionally distinct antibody claimed; and/or (3) the claimed antibody's amino acid or nucleic acid sequence is an unpredictable event. Castan, A., et. al., (Biopharmaceutical Processing: Chapter 7 – Cell Line Development, (Elsevier), 131-146; Published 2018), hereby Castan, teaches that homogenous cell population derived from single cell is important towards biopharmaceutical production, wherein a heterogenous pool will have different clones contributing to the product (page 136, second paragraph). It is further taught that a thorough understanding and characterization of the clone used is needed (page 136, third paragraph). Therefore, it would require undue experimentation to reproduce the claimed cell line, i.e., 293TD37. Deposit of the cell line would satisfy the enablement requirements of 35 U.S.C. § 112, first paragraph. See 37 C.F.R. 1.801-1.809.
If the deposit is made under the provisions of the Budapest Treaty, filing of an affidavit or declaration by Applicant or assignees or a statement by an attorney of record who has authority and control over the conditions of deposit over his or her signature and registration number stating that the deposit has been accepted by an International Depository Authority under the provisions of the Budapest Treaty and that all restrictions upon public access to the deposited material will be irrevocably removed upon the grant of a patent on this application. This requirement is necessary when deposits are made under the provisions of the Budapest Treaty as the Treaty leaves this specific matter to the discretion of each State.
If the deposit is not made under the provisions of the Budapest Treaty, then in order to certify that the deposits comply with the criteria set forth in 37 CFR 1.801-1.809 regarding availability and permanency of deposits, assurance of compliance is required. Such assurance may be in the form of an affidavit or declaration by Applicants or assignees or in the form of a statement by an attorney of record who has the authority and control over the conditions of deposit over his or her signature and registration number averring:
during the pendency of this application, access to the deposits will be afforded to the Commissioner upon request;
all restrictions upon the availability to the public of the deposited biological material will be irrevocably removed upon the granting of a patent on this application;
the deposits will be maintained in a public depository for a period of at least thirty years from the date of deposit or for the enforceable life of the patent of or for a period of five years after the date of the most recent request for the furnishing of a sample of the deposited biological material, whichever is longest; and
the deposits will be replaced if they should become nonviable or non-replicable.
Amendment of the specification to recite the date of deposit and the complete name and address of the depository is required. As an additional means for completing the record, Applicant may submit a copy of the contract with the depository for deposit and maintenance of each deposit. The mere indication that a deposit has been made under conditions prescribed by the Budapest Treaty would satisfy all conditions of these regulations except the requirement that all restrictions on access be removed on grant of the patent. Ex parte Hildebrand, 15 USPQ2d 1662 (Bd. Pat. App. & Int. 1990).
If a deposit is made after the effective filing date of the application for patent in the United States, a verified statement is required from a person in a position to corroborate that the biological material described in the specification as filed is the same as that deposited in the depository, stating that the deposited material is identical to the biological material described in the specification and was in the Applicant's possession at the time the application was filed.
35 USC § 112(a) – Scope of Enablement
21. Claims 10 – 14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the specific combinations of tested antigens shown to function therapeutically or prophylactically, i.e., a therapeutic composition which expresses four antigens that are immunogenic or vaccine that contains at least one antigen that makes neutralizing antibodies thereto, does not reasonably provide enablement for merely any antigen or antigen combination causing an immune response that will generate neutralizing antibodies and thus function as a vaccine, preventing viral infection. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit has developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors, to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." The factors considered include, but are not limited to, (A) the breadth of the claims; (B) the nature of the invention; (C) the state of the prior art; (D) the level of one of ordinary skill in the art; (E) the level of predictability in the art; (F) the amount of direction provided by the inventor; (G) the existence of working examples; and (H) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Breadth of the claims and nature of the invention: Claims 10 – 14 are drawn to an ASFV vaccine that is obtained by co-expressing four antigen genes of the ASFV in a recombinant adenovirus vector (rAAV). Further limitations include that the four antigens are selected from five different groups, wherein one of the groups include P72, B602L, P30, and P54. In the instant specification, it is taught that P30 is one of the most antigenic ASFV proteins can induce host cells to produce neutralizing antibodies that inhibit intracellular internalization (pages 2 and 3). It is further taught that P54 has virus neutralization abilities, P72 is one of the main detected antigens of ASFV, and PB602L stimulates the production of high-level antibodies (page 3). For the other four groups, the four antigens per group were selected from a list of antigen genes with stronger immune effect, then grouped according to the size of the gene fragment and protein structure so they could be co-expressed completely and independently in the designed vector (page 3). At a minimum, the claims encompass a vaccine that elicits a neutralizing antibody response against ASFV. However, the specification only provides sufficient disclosure for the five different groups of antigen genes, constituting the different rAAVs, inducing a CD8+ T-cell and CD4+ T-cell immune response, wherein the expression levels of IFNγ, TNFα, and IL2 in the immunization group were significantly higher over the control group (examples 12, 13, 22, 31, 40, and 48).
State of the prior art and unpredictability in the art: According to the specification of the claimed
invention, there are no recombinant adenovirus vectors for co-expression of P72, B602L, P30, and P54 of ASFV to be applied to the development of live vector vaccines (page 3). The specification also discloses there is no combination of two molecular adjuvants simultaneously cloned into the vector and coexpressed with a group of ASFV antigens.
However, Goatley, L. C., et. al., (A Pool of Eight Virally Vectored African Swine Fever Antigens Protect Pigs Against Fatal Disease. Vaccines, 8(2), 234; Published 05/18/2020), hereby Goatley, teaches that in the art, numerous combinations of different antigen genes, and their associated proteins, resulted in vaccine-induced enhanced disease (page 2, second paragraph). It is further taught by Goatley that a recombinant ASFV vaccine of P30, P72, P54, and P22 induced neutralizing antibodies in pigs, but did not protect animals from fatal disease (page 2, first paragraph). A pool comprised of genes including A151R, B646L (p72), CP204L (p30), CP530R (pp62), E146L, I73R, I215L, L8L, and MGF110-4L, among others, is taught to have reduced clinical signs and reduced levels of viremia in a proportion of pigs (page 2, second paragraph; underline added to emphasize genes disclosed in instant claims). It is further taught by Goatley that a pool of eight antigen genes, including B602L, B646L, CP204L, E183L, E199L, EP153R, F317L, and MGF505-5R, are required for protection and induced ASFV-specific IFNγ-secreting cells (page 8; page 20, last paragraph; underline added to emphasize genes disclosed in instant claims). This was in contrast to a pool of eight antigen genes, including B602L, EP153R, EP364R, F317L, I329L, MGF360-11L, MGF505-4R, and MGF505-5R, and a pool of five antigen genes, including B646L, CP204L, E199L, F317L, and MGF505-5R. It is speculated by Goatley that B602L, E183L, and EP153R are important protective antigens based on their absence in the third pool of antigens (page 20, last paragraph). Moreover, Goatley goes on to teach that some antigen genes, including EP402R, will not elicit protection unless they are fused to ubiquitin (page 2, first paragraph). In fact, EP402R, in combination with CP204L and E183L did not protect animals from fatal disease despite inducing antigen-specific responses, but rather antibodies directed to EP402R resulted in enhanced disease (page 2, first and second paragraph). It is taught that live attenuated viruses suggest a role for both humoral and cellular responses in protection against virulent strains of ASFV (page 2, second paragraph). Goatley goes on to teach that it is difficult to predict cross-protection between ASFV isolates (page 21, second paragraph). Importantly, it is not clear from the prior art or instant specification that the disclosed groups of antigens elicit neutralizing antibodies, while not inducing illness, and so would be capable of meeting the claim limitations to their full scopes.
Further in the art, Neilan, J. G., et. al., (Neutralizing antibodies to African swine fever virus proteins p30, p54, and p72 are not sufficient for antibody-mediated protection. Virology, 319(2), 337–342; Published 11/07/2003), hereby Neilan, teaches that virus neutralizing epitopes have been identified on p30, p54, and p72 (page 337, abstract). It is further taught that neutralizing antibodies to these ASFV proteins is insufficient for antibody-mediated protection against clinical disease or even death (page 337, abstract; page 339, right column, third paragraph). In fact, immunization of swine with p22, p30, p54, and p72 had no effect on disease development, progression, or outcome, despite antibodies to all proteins in the sera (page 339, left column, first paragraph; page 339, right column, first paragraph). Neilan goes on to teach that ASF antibody-mediated protection is a complex event requiring multiple responses to many different viral protein, wherein individual protective antigens are difficult to demonstrate experimentally (page 339, right column, last paragraph).
To summarize, the prior art, as of 06/30/2023, does not provide evidence for safe vaccination against ASFV using the disclosed combinations of antigens, but does teach a recombinant adenovirus can be utilized with a pool of antigen genes to induce a protective immune response against ASFV, wherein ubiquitin can be used as an adjuvant. The art also teaches that while specific antigen genes have a higher likelihood of inducing protection from severe disease, some can result in vaccine-induced enhanced disease. Further in the art, it is also taught that neutralizing antibodies themselves are insufficient for antibody-mediated protection against ASFV.
Taken together, the art teaches that while there are ASFV viral genes/proteins that elicit neutralizing antibodies and other immune responses, these are insufficient to confer protective immunity to viral challenge, including p30, p54, pp62, p72, A151R, B602L, E146L, I73R, I215L, L8L, and MGF110-4L. Additionally, it is taught that some antigen genes, including EP153R, result in vaccine-induced enhanced disease. It is thus unpredictable as to what combinations of ASFV proteins can be administered in a vaccine to elicit a protective immune response, even if neutralizing antibodies or other immune responses are demonstrated.
Those with relevant skill in the art: The level of skill in the art is that of Ph.D.-level scientists and
medical doctors (D.O. and/or M.D.).
Amount of direction and existence of working examples: The instant application teaches five working examples, which does not represent neutralizing antibodies elicited by the different compositions; or the lack of vaccine-enhanced disease when employing antigens known to cause the disease state. Thus, the instant application offers no reasonable guidance or direction to use the claimed method for vaccinating a patient against ASFV.
The closest working example to the first group, i.e., pAd5LCL3-P72-B602L-P30-P54 and its associated antigen genes, is in examples 9 – 13 on pages 47 – 52 and figures 49 and 57 – 61, hereby referred to as example 1. Example 1 teaches that pAd5LCL3-P72-B602L-P30-P54 was grown and stably packaged in 293TD37 cells. Mice challenged with the example 1 vaccine produced high concentrations of IgG antibodies to P72 and P30 proteins. It is further taught that vaccination induced CD8+ T-cell and CD4+ T-cell immune responses, wherein the expression levels of IFNγ, TNFα, and IL2 in the immunization group were significantly higher over the control group. Vaccination also resulted in high levels of cytotoxic T cells. However, example 1 is silent as to whether IgG antibodies were elicited to PB602L, as encoded by B602L, and P54.
The closest working example to the second group, i.e., pAd5LCL3-CP129Rubiqutin-MGF5L6L-CP312R-MGF110-4L and its associated antigen genes, is in examples 17 – 22 on pages 60 – 63 and figures 96 – 99, hereby referred to as example 2. Like example 1, example 2 teaches that pAd5LCL3-CP129Rubiqutin-MGF5L6L-CP312R-MGF110-4L was grown and stably packaged in 293TD37 cells. Mice challenged with the example 2 vaccine had high expression levels of IFNγ, TNFα, and IL2 in CD8+ T-cell and CD4+ T-cells. Example 2 is silent, however, as to IgG antibodies or the cytotoxic T cell response elicited by the vaccine.
The closest working example to the third group, i.e., pAd5LCL3-L8Lubiqutin-I215L-I73RHBsAg-E146L and its associated antigen genes, is in examples 28 – 31 on pages 71 – 73 and figures 126 – 129, hereby example 3. Example 3 teaches that pAd5LCL3-L8Lubiqutin-I215L-I73RHBsAg-E146L was grown and stably packaged in 293TD37 cells. Like examples 1 and 2, mice challenged with the example 3 vaccine had high expression levels of IFNγ, TNFα, and IL2 in CD8+ T-cell and CD4+ T-cells. Example 3 is silent, however, as to IgG antibodies or the cytotoxic T cell response elicited by the vaccine.
The closest working example to the fourth group, i.e., pAd5LCL3-EP402R-EP153R-I177L-K205Rubiqutin and its associated antigen genes, is in examples 37 – 40 on pages 80 – 83 and figures 154 – 157, hereby example 4. Example 4 teaches that pAd5LCL3-EP402R-EP153R-I177L-K205Rubiqutin was grown and stably packaged in 293TD37 cells. Mice challenged with the example 4 vaccine produced high concentrations of IgG antibodies to EP402R. It is further taught that vaccination induced CD8+ T-cell and CD4+ T-cell immune responses, wherein the expression levels of IFNγ, TNFα, and IL2 in the immunization group were significantly higher over the control group. However, example 4 is silent as to whether IgG antibodies were elicited to EP153R, I177L, and K205R or the cytotoxic T cell response elicited by the vaccine. Moreover, example 4 fails to teach whether or not vaccination resulted in vaccine-induced enhanced disease, wherein EP402 is known in the art to cause the disease state.
The closest working example to the fifth group, i.e., pAd5LCL3-F317L-A151R-P34-pp62 and its associated antigen genes, is in examples 46 – 49 on pages 89 – 92 and figures 184 – 187, hereby example 5. Example 5 teaches that pAd5LCL3-F317L-A151R-P34-pp62 was grown and stably packaged in 293TD37 cells. Mice challenged with the example 5 vaccine produced high concentrations of IgG antibodies to pp62. It is further taught that vaccination induced CD8+ T-cell and CD4+ T-cell immune responses, wherein the expression levels of IFNγ, TNFα, and IL2 in the immunization group were significantly higher over the control group. However, example 5 fails to teach if IgG antibodies were elicited for F217L, A151R, and P34.
The instant application has no examples of neutralizing antibodies that are elicited for the vaccines in examples 2 and 3. While IgG antibodies were elicited for examples 1, 4, and 5, it was not disclosed whether these were neutralizing or non-neutralizing antibodies. Additionally, not all antigen genes in examples 1, 4, and 5 were demonstrated to have IgG antibodies. Moreover, the safety and efficacy of the compositions are not disclosed. For example, there is no guidance as to whether or not vaccine-induced enhanced diseases would arise, particularly for compositions including antigen genes known to elicit the disease state, including EP402R in the fourth group.
Quantity of experimentation needed: Reasonable guidance with respect to preventing any cancer relies on quantitative analysis from defined populations that have been successfully pre-screened and are predisposed to particular types of cancer. This type of data might be derived from widespread genetic analysis, cancer clusters, or family histories. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of clinical cancer and link those results with subsequent histological confirmation of the presence or absence of disease. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent. Furthermore, a preventive administration also must assume that the therapeutic will be safe and tolerable for anyone susceptible to the disease. In the case of virus vaccines, a reasonable nexus exists between neutralizing antibody generation and prevention of infection. Thus, a showing that an antigen can produce such antibodies would support enablement for use of said antigen in a vaccine and/or method of preventing infection of the virus comprising said antigen.
Riddell, M. A., et. al., (Identification of immunodominant and conformational epitopes in the capsid protein of hepatitis E virus by using monoclonal antibodies. Journal of virology, 74(17), 8011–8017; Published 05/30/2000), hereby Riddell, teaches that antibodies in patient sera will react with some, but not all, B-cell epitopes on the ORF2.1 antigen (page 8011, abstract). Thus, not just any epitope/antigen/immunogen will contribute to a subject’s immunity against a virus, which is required for prevention. Moreover, Sugiyama, M., et. al., (Identification of immunodominant neutralizing epitopes on the hemagglutinin protein of rinderpest virus. Journal of virology, 76(4), 1691–1696; Published 11/15/2001), hereby Sugiyama, supports Riddell by teaching that even amongst known epitopes that lead to neutralizing antibodies in some species, another subject’s immune reaction will not necessarily generate antibodies against all said antibodies (1691, abstract). Goatley teaches similarly for ASFV, wherein two of the subject’s had consistently higher IFNγ cells in circulation than the other subject’s that were vaccinated with the same pool of antigen genes (page 8). Goatley further teaches that neutralizing antibodies are insufficient to protect pigs from severe or fatal disease (page 2, second paragraph).
In the instantly claimed invention, there would be undue experimentation to determine if the described epitopes contained within the vaccine of the instant claims can elicit a neutralizing antibody. Moreover, it would require undue experimentation to determine the safety and efficacy of antigen genes that are known to cause vaccine-induced enhanced disease. It is also unpredictable as to whether or not the different combinations of ASFV proteins will confer protective immunity, even if neutralizing antibodies or other immune responses occur.
For these reasons, undue experimentation would be required to practice the claimed invention commensurate with the scope of the claims, as discussed above. Reasonable correlation must exist between the scope of the claims and scope of enablement set forth. It would take undue trials and errors to practice the claimed invention in view of the quantity of experimentation necessary, the limited working examples, the unpredictability of the art, the lack of sufficient guidance in the specification, and the breadth of the claims.
Conclusion: The instant disclosure is not enabling for any antigen or antigen combination of ASFV genes/proteins that prevents infection, but rather a therapeutic immunogen with one of the set forth groups, wherein at least one antigen in the group must have been demonstrated to make neutralizing antibodies. The genes possessed by Applicant that are known in the art to produce neutralizing antibodies are P30, P72, and P54. Neutralizing antibodies directed towards the other claimed antigen genes must therefore be taught in the instant disclosure. However, the instant disclosure only teaches that some antigen genes, i.e., P72 and P30 (first group); EP402 (fourth group); pp62 (fifth group), elicit IgG antibodies, but does not disclose if these are neutralizing or nonneutralizing antibodies. No neutralizing antibodies are taught by the prior art or instant disclosure for any antigen gene in the second – fifth group. Thus, only the first group of ASFV antigen genes are enabled, i.e., P30, P72, P54, and B602L, to make and use a vaccine against ASFV as presently written.
Claim Rejections - 35 USC § 103
22. 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.
23. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
24. Claims 10 – 14 are rejected under 35 U.S.C. 103 as being unpatentable over Neilan, J. G., et. al., (Neutralizing antibodies to African swine fever virus proteins p30, p54, and p72 are not sufficient for antibody-mediated protection. Virology, 319(2), 337–342; Published 11/07/2003), hereby Neilan, in view of Goatley, L. C., et. al., (A Pool of Eight Virally Vectored African Swine Fever Antigens Protect Pigs Against Fatal Disease. Vaccines, 8(2), 234; Published 05/18/2020), hereby Goatley, and Lopera-Madrid, J., et. al. (Safety and immunogenicity of mammalian cell derived and Modified Vaccinia Ankara vectored African swine fever subunit antigens in swine. Veterinary immunology and immunopathology, 185, 20–33; Published 01/23/2017), hereby Madrid.
The claim limitation of “the vaccine is obtained by constructing a recombinant adenovirus vector…” in claims 10 and 11 is being interpreted herein as a product-by-process. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
"[T]he lack of physical description in a product-by-process claim makes determination of the patentability of the claim more difficult, since in spite of the fact that the claim may recite only process limitations, it is the patentability of the product claimed and not of the recited process steps which must be established. We are therefore of the opinion that when the prior art discloses a product which reasonably appears to be either identical with or only slightly different than a product claimed in a product-by-process claim, a rejection based alternatively on either section 102 or section 103 of the statute is eminently fair and acceptable. As a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith." In re Brown, 459 F.2d 531, 535, 173 USPQ 685, 688 (CCPA 1972).
Claims 10 and 11 are drawn to the construction of the recombinant adenovirus in a transformed HEK293 cell line and not a method of making the same (instant specification, page 4). For purposes of applying prior art, claims 10 and 11 are broadly interpreted here to encompass any HEK293 cell line that can express an adenovirus vector with four ASFV antigen genes.
Neilan teaches the construction of a recombinant baculovirus that encodes four genes, and subsequently expresses, four ASFV proteins: p30, p54, p72, and p22 (page 338, right column, first paragraph; page 340, left column, last paragraph; underline added to emphasize those found in the instant claims – first group), as recited in instant claims 10 – 14. It is further taught that the four ASFV proteins in the recombinant baculovirus were successfully expressed in infected Sf21 cells, i.e., an insect cell line (page 338, right column, second paragraph, figure 1; page 340, left column, second paragraph), as broadly defined in instant claims 10 and 11. Neilan goes on to teach that swine challenged/immunized with the ASFV proteins had neutralizing antibodies to all four proteins in their sera, but did not have protective immune responses (page 339, left column, first paragraph). However, vaccines can also be therapeutic and generation of these antibodies would at least indicate the vaccination can treat ASFV.
Neilan does not teach the usage of an adenovirus vector to express the ASFV proteins, as required in instant claims 10 – 14. However, Goatley teaches the construction of replication-deficient rAAV vectors encoding numerous ASFV genes that are cloned into pcDNA3.1zeo(+) and grown in Vero cells (page 3, second and third paragraphs), as required in instant claims 10 – 14. It is further taught that three groups of different ASFV antigen genes induced virus- and antigen-specific immune responses: B602L, B646L (p72), CP204L (p30), E183L (p54), E199L, EP153R, F317L, and MGF505-5R; B602L, EP153R, EP364R, F317L, I329L, MGF360-11L, MGF505-4R, and MGF505-5R; and B646L, CP204L, E199L, F317L, and MGF505-5R (page 5, table 1; page 12, second paragraph; page 16, third paragraph; underline added to emphasize those found in the instant claims), as defined in instant claims 12 – 14. Goatley also teaches that ubiquitin is a common adjuvant employed with ASFV genes (page 2, first paragraph), as recited in instant claims 12 – 14.
Neither Neilan or Goatley teaches the usage of HEK293 cells to express the ASFV proteins, as broadly encompassed by instant claims 10 – 14. However, Madrid teaches that recombinant ASFV antigens can be safely expressed in HEK293 cells (page 20, abstract; page 22, left column, third paragraph; page 24, left paragraph), as defined in instant claims 10 – 14. It is further taught that swine vaccinated with HEK293-derived genes had significantly higher IgG responses over those expressed by alternative methods (page 24, right column, fifth paragraph).
Neilan, Goatley, and Madrid do not explicitly teach the combination of the antigen genes as set forth in instant claims 12 – 14. However, Neilan teaches the construction of a vector that expresses four ASFV antigen genes: p30, p54, p72, and p22 (page 338, right column, first paragraph; page 340, left column, last paragraph). Goatley teaches a vector that expresses eight ASFV antigen genes, including B646L (p72), E183L (p54), and B602L (page 5, table 1; page 12, second paragraph; page 16, third paragraph). Thus, "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023). In light of this case law, it would have been obvious a person having ordinary skill in the art to combine p30, p54, p72, and B602L, into one vector to create a predictably functional therapeutic vaccine against ASFV, i.e., the first group of the instant claims.
Neilan, Goatley, and Madrid are considered to be analogous to the claimed invention because all are drawn to the expression and immunogenicity of different ASFV antigens. Based on the prior art teachings, it would have been obvious to a person having ordinary skill in the art to express the four ASFV antigen genes of Neilan in the HEK293 cells of Madrid using the replication-deficient rAAV, plasmid, and adjuvant taught by Goatley. This obviousness is mainly owed to Neilan teaching the expression of four ASFV antigen genes that Goatley and Madrid make improvements thereof in an attempt to elicit a protective immune response. Therefore, it would have been obvious to a person having ordinary skill in the art to have combined the teachings of Neilan, Goatley, and Madrid before the effective filing date of the claimed invention with a reasonable expectation of success to provide an adenovirus-vectored vaccine in mammalian cells that is more potent, at least as a therapeutic agent, against AFSV due to an induction of both humoral and cell-mediated immunity (Neilan; page 31, left column, first and third paragraph). All the claimed elements were known in the prior art. The simple substitution of one known element for another is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415–421, 82 USPQ2d 1385, 1395–97 (2007) and MPEP §§ 2143B and 2143.02.
Conclusion
26. Claims 10 – 14 are rejected. No claims are allowed.
27. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Hallie N. Pennington, Ph.D. whose telephone number is (571)272-6781. The Examiner can normally be reached M-Th 7:30-5:30 ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, Applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Michael Allen can be reached at (571)270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HALLIE N. PENNINGTON, PH.D./Examiner, Art Unit 1671
/Michael Allen/Supervisory Patent Examiner, Art Unit 1671