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 .
Claim Status
Claims 70-89 are pending and under consideration.
Claim Objections
Claim 70 is objected to because of the following informalities: It is suggested that Applicant amend
“wherein the antigen comprises a circumsporozoite (CS) protein or a fragment thereof and a hepatitis B surface antigen (HBsAg) or a fragment thereof” to
“wherein the antigen comprises (i) a circumsporozoite (CS) protein or a fragment thereof and (ii) a hepatitis B surface antigen (HBsAg) or a fragment thereof” for better clarity because mixed use of conjunction “and” and “or” may cause confusion. Appropriate correction is required.
Claim 75 is objected to because of the following informalities: “iscom” should read “ISCOM” because acronyms must be capitalized. Furthermore, “ISCOM” must be spelled out on its first use. Appropriate correction is required.
Claims 75-76 are objected to because of the following informalities: “Quillaja Saponaria” should read “Quillaja saponaria” because binomial nomenclature must be in italics and species name must be in lower case. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 84-85 and 87-89 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.
Claim 84 recites administering a fourth dose. However, claim 79 does not recite a third dose. Therefore, it is unclear how can a fourth dose can be administered without a third dose. Furthermore, claim 84 recites conjunction “or” before tenth dose. Therefore, claim 84 encompasses only one among fourth to tenth dose. It is unclear how fourth, fifth, sixth, seventh, eighth, ninth or tenth dose can be administered without previous doses.
Claim 85 depends from claim 1 which was already canceled. Hereinafter, claim 85 will be interpreted as if it depends from claim 70.
Claim 87 recites “up to about 2 months, up to about 2.5 months, … , up to about 12 months” in line 11-16. Claim language “up to” is used to set the required maximum number for the range. However, when it is used together with claim language “about”, the language “up to about” makes claim indefinite because the required maximum number is not clear.
Claims 88-89 recite “at least about 12 months”, “at least about 77%”, and “at least about 24 months”. Claim language “at least” is used to set the required minimum number for the range. However, when it is used together with claim language “about”, the language “at least about” makes claim indefinite because the required minimum number is not clear.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 70-89 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a “written description” rejection.
“[T]he 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.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, 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. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Regents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., binding to antigen, high affinity, neutralization activity, competing with a reference antibody for binding), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
“[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For antibodies, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor, 97 USPQ2d at 1875 (“[T]he application only provides amino acid sequence information (a molecular description of the antibody) for a single mouse variable region, i.e., the variable region that the mouse A2 antibody and the chimeric antibody have in common. However, the mouse variable region sequence does not serve as a stepping stone to identifying a human variable region within the scope of the claims.”). A chimeric antibody shares the full heavy and light chain variable regions with the corresponding mouse antibody; that is, the structure shared between a mouse and chimeric antibody would generally be expected to conserve the antigen binding activity.
Even if a selection procedure is disclosed that was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad, 94 USPQ2d at 1167; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
Additionally, “An adequate written description must contain enough information about the actual makeup of the claimed products—“a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials,” which may be present in “functional” terminology “when the art has established a correlation between structure and function.” Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies.” Amgen Inc v. Sanofi 124 USPQ2d 1354, 1361 (Fed. Cir. 2017). “Further, the “newly characterized antigen” test flouts basic legal principles of the written description requirement. Section 112 requires a “written description of the invention.” But this test allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen. The test thus contradicts the statutory “quid pro quo” of the patent system where “one describes an invention, and, if the law's other requirements are met, one obtains a patent.” Ariad, 598 F.3d at 1345.” Amgen at 1362.
Claim Analysis
Instant claims are drawn to a method of stimulating an immune response against a Plasmodium parasite in a subject comprising administering an immunogenic composition comprising an antigen of a Plasmodium parasite, wherein the antigen comprises a circumsporozoite (CS) protein or a fragment thereof and a hepatitis B surface antigen (HBsAg) or a fragment thereof.
Instant specification disclosed an immunogenic composition comprising an R21 protein and saponin adjuvant (example 1-4, page 35-48). R21 protein is a fusion protein comprising CS protein and HBsAg (instant Figure 8). Instant SEQ ID NO: 1 and SEQ ID NO: 2 are amino acid sequences for R21 protein. In contrast, instant claim 70 encompasses any antigen comprising any fragments of two protein CS and HBsAg. The limitation “fragments thereof” recited by instant claim 70 encompasses any fragment of the protein which can be even two amino acid residues. Although instant specification showed that specific fusion protein R21 with SEQ ID NO: 1 and 2 can stimulate immune response against Plasmodium parasite, instant specification did not show that any antigen comprising any fragments of CS and HBsAg proteins can stimulate immune response against Plasmodium parasite.
Instant claim 71 recites 99.5% sequence identity to SEQ ID NO: 1 or SEQ ID NO: 2. Because SEQ ID NO: 1 and 2 have 410 and 414 residues, respectively, the allowed 0.5% variation of SEQ ID NO: 1, for example, corresponds to 4 amino acid mutations in SEQ ID NO: 1. The possible combination of selecting 4 amino acid positions out of 410 residues of SEQ ID NO: 1 is (410, 4) = 410!/((410-4)!x4!) = (410x409x408x407)/(4x3x2x1) = 1.16x109. For each combination, the possible number of mutants in the selected position is 204 – 1 (wild type) = 1.6x105. Therefore, instant claim 71 encompasses at least (1.16x109) x (1.6x105) = 1.86 x 1014 variant of SEQ ID NO: 1. Same reasoning applies to SEQ ID NO: 2. Therefore, only two species R21 protein with SEQ ID NO: 1 and 2 cannot be considered as a representative number of species falling within the scope of genus encompassing at least 1.86 x 1014 variant of SEQ ID NO: 1 or 2. Among these variants, mutations in critical amino acids to stimulate immune response against Plasmodium parasite are included and one of ordinary skill in the art would not be able to predict that these variants will still be able to stimulate immune response against Plasmodium parasite.
In the field of protein modification technology, a change of a single amino acid residue may change the properties of the protein. Sickle cell anemia, for example, results from a mutation in just one of 574 amino acids. For example, Prengler et al (Ann Neurol 2002;51:543-552; PTO-892) teaches that one amino acid substitution valine for glutamic acid at the sixth position of the beta-globin chain cause sickle cell anemia (page 544, left column, third paragraph). Therefore, one of ordinary skill in the art would not be able to predict that any variants among allowed 0.5% variation in SEQ ID NO: 1 or 2 will still have same property of stimulating immune response as SEQ ID NO: 1 or 2.
The disclosure therefore does not show that applicant was in possession of the necessary common attributes or features possessed by the members of the claimed genus. Accordingly, the skilled artisan would not recognize that applicants were in possession of the invention as broadly claimed at the time the application was filed.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 70-76, 78-82 and 85-89 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hill et al (WO2019/021013; 8/14/2025 IDS).
Regarding claims 70-71, 78, and 85-86, Hill teaches “A method of immunisation of a human subject susceptible to Plasmodium falciparum infection comprising administering a composition comprising polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO: 1, or a sequence having at least 80%, 85%, 90%, 95%, 98%, or 99% sequence identity to SEQ ID NO: 1 (R21), wherein said polypeptide is in the form of a virus-like particle (VLP), wherein said particle comprises less than 10% free hepatitis B surface antigen protein, to said subject, wherein said composition is administered in a dosage regimen of at least one dose of 1 μg to 20 μg R21 per administration for a subject at least 18 years old, or at least one dose of 0.5 μg to 10 μg R21 per administration for a subject less than 18 years old.” (claim 27). SEQ ID NO: 1 of Hill is 100% identical to instant SEQ ID NO: 1 (SCV; duplicate of Result 1 of 1.rag). Because instant SEQ ID NO: 1 is fusion protein of CS protein from P.falciparum and HBsAg (instant specification, paragraph 0047; instant Figure 8), the R21 protein of Hill also comprises CS protein from P.falciparum and HBsAg. Hill teaches R21 with a C-terminal extension tag (R21c), SEQ ID 2 which is 100% identical to instant SEQ ID NO: 2 (SCV; Result 1 of 2.rag).
Regarding claim 72, claim 28 of Hill teaches that said composition further comprises an adjuvant, wherein said adjuvant is Matrix-M, and wherein said adjuvant is present in a ratio in the range 1:1 to 1:50 of R21:Matrix-M.
Regarding claim 73-74, Hill teaches “Most suitably said dose comprises 25 to 50 μg adjuvant for a subject at least 18 years old”.
Regarding claims 75-76, Hill teaches “The adjuvant may be a squalene-based adjuvant and/or an ISCOM-based adjuvant, such as Abisco/Matrix M (from Isconova, Uppsala - now 'Novavax AB' (instant assignee)). Abisco-ioo (known as Matrix-M when made to GMP standard) has the following chemical content: purified saponins obtained from a crude extract of the plant Quillaja saponaria Molina; cholesterol from Lanolin and phosphatidyl choline (phospholipid) from fresh egg yolk; in a suspension of nano-sized (40 nm) cage-like particles consisting of the above ingredients, in PBS.
Matrix M (or Abisco-100) consists of a mixture of Matrix A (corresponds to “first ISCOM particle of instant claim 75”) and Matrix C (corresponds to “second ISCOM particle of instant claim 75”) at a ratio of 80:20 to 95:5, preferably 85:15. Matrix A leads to T cell induction and has low toxicity, Matrix C induces antibodies and has some toxicity. Matrix C contains C fraction of QS separation which corresponds to QS21. Fraction A (in Matrix A) corresponds to QS7.”
Regarding claim 79-81, Hill teaches “For the final dose (i.e. the second dose in a two dose regimen and the third dose in a three dose regime) the R21 amount may be reduced 2 - 10 fold, most suitably reduced 5 fold.” Therefore, Hill teaches two-dose regimen as recited by instant claim 79 and three-dose regimen as recited by instant claim 80.
Regarding claim 82, Hill teaches “In other embodiments each dose has the same R21 amount.”
Regarding claims 87-89, as discussed above, because Hill teaches administering antigen with same sequence as instant SEQ ID NO: 1 and 2, the antigen of Hill will have same functional property as recited by instant claims 87-89.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 70-76 and 78-89 are rejected under 35 U.S.C. 103 as being unpatentable over Hill et al (WO2019/021013; 8/14/2025 IDS) in view of Kumar et al (WO2010/036293; PTO-892) and Clements et al (WO2007/006052; PTO-892).
Regarding claims 70-76, 78-82 and 85-89, teachings of Hill were discussed above in 102 section.
However, Hill does not teach that the second dose is administered one month after the first dose and regimen up to fourth dose as claimed by instant claims 83-84.
Regarding claim 83, Kumar teaches methods to prevent the transmission of malaria using the immunogenic compositions (abstract). Kumar teaches “The vaccine, dose, route and schedules selected were based on experience with numerous other malaria vaccine trials in nonhuman primates. Here, the vaccine was delivered through the intramuscular route (quadriceps, two sites) and boosted twice with the same dose of protein at 4 and 12 weeks post primary immunization [Fig 4a].” Figure 4A of Kumar was reproduced below. The first boost of Kumar corresponds to the second dose of instant invention. Therefore, Kumar teaches that the second dose is administered about 1 month after the first dose.
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Regarding claim 84, Another reference Clements also teaches Malaria vaccine (abstract). Clements teaches “Rabbits were bled two weeks after the first three doses and at three and four weeks after the fourth dose.” Therefore, Clements teaches dosing regimen up to fourth dose of Malaria vaccine.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered the second dose about 1 month after the first dose because Kumar teaches that the second dose of malaria vaccine can be administered 1 month after the first dose for the effective malaria vaccination. It would have also been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered Malaria vaccine up to fourth dose because Clements teaches dosing regimen up to fourth dose of Malaria vaccine can be effectively applied for Malaria vaccination. One of ordinary skill in the art would be motivated to test these dosing regimens to see if these dosing regimens can be effective also with R21 Malaria vaccine of Hill because Kumar and Clements teach that these dosing regimens can be effectively applied for Malaria vaccination. Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success because Kumar and Clements teach that these dosing regimens can be effectively applied for Malaria vaccination. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 70-82 and 85-89 are rejected under 35 U.S.C. 103 as being unpatentable over Hill et al (WO2019/021013; 8/14/2025 IDS) in view of Edwards et al (WO2012/103303; PTO-892).
Regarding claims 70-76, 78-82 and 85-89, teachings of Hill were discussed above in 102 section.
However, Hill does not teach administering the immunogenic composition in a prefilled syringe.
Regarding claim 77, Edwards teaches administration of a medicament within a prefilled syringe (title). Claim 13 of Edwards teaches that the medicament container is a prefilled syringe containing malaria vaccine. Therefore, Edwards teaches that prefilled syringe can be effectively used for malaria vaccination.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered malaria vaccine composition in a prefilled syringe because Edwards teaches that prefilled syringe can be effectively used for malaria vaccination. One of ordinary skill in the art would be motivated to use prefilled syringe because one of ordinary skill in the art would understand that prefilled syringe provides convenience for vaccination at clinic because it removes the step of transferring vaccine composition from storage bottle to syringe for injection. Furthermore, prefilled syringe would prevent possible contamination during the transfer due to unclean bottle cap. Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success because Edwards teaches that prefilled syringe can be effectively used for malaria vaccination. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
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/CHEOM-GIL CHEONG/Examiner, Art Unit 1645
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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