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SEBBEL et al 
Appl. No. 09/848,616 



Remarks 

L Status of the Claims and Support for Amendments 

By the forgoing amendments, claims 1-27, 32, 33, 39, 40, 45-47, 57-60, 63-77, 81, 
82 and 87-89 have been cancelled without prejudice thereto or disclaimer thereof, as reading, 
at least in part, on non-elected species. Applicants reserve the right to prosecute the subject 
matter of these claims in one or more continuing applications. 

The amendments to claims 90, 91, 93, 97, 98, 106 and 108 are sought to be entered 
to provide the correct dependency for these claims upon cancellation of claims 87-89. 
Hence, no new matter is added by the foregoing amendments and their entry and 
consideration are respectfully requested. Upon entry of the foregoing amendments, claims 86 
and 90-1 10 are pending in the application, with claim 86 being the sole independent claim. 

77. Summary of the Office Action 

In the Office Action dated October 3 1 , 2003, the Examiner has withdrawn claims 87- 
89 from consideration, and has made five rejections of the claims. Based on the following 
remarks, Applicants respectfully request that the Examiner reconsider all outstanding 
rejections and that they be withdrawn. 

///. The Withdrawal of Claims 87-89 

In the Office Action at page 2, the Examiner has withdrawn claims 87-89 from 
consideration under 37 C.F.R. § 1 .142(b) as allegedly being drawn to a nonelected species. 
Applicants respectfully traverse this withdrawal. However, for reasons unrelated to this 



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action and not in acquiescence thereto, claims 87-89 have been cancelled without prejudice 
or disclaimer. Hence, the withdrawal of these claims has been rendered moot. 

IV. The First Rejection Under 35 U.S. C. § 103(a) 

In the Office Action at pages 2-3, the Examiner has rejected claims 86, 90-94 and 96- 
107 under 35 U.S.C. § 103(a), as being unpatentable over Birkett et al (U.S. Patent No. 
6,23 1 ,864; document "A" cited on the Form PTO-982 attached to Paper No. 1 1 and Doc. No. 
AE2, of record; hereinafter "Birkett"), in view of Mark et al (U.S. Patent No. 4,959,314; 
document "C" cited on the Form PTO-892 attached to Paper No. 1 1 ; hereinafter "Mark") and 
Zhou et al (document "Z" cited on the Form PTO-892 attached to Paper No. 1 1 ; hereinafter 
"Zhou"). Applicants respectfully traverse this rejection. 

A. The Cited References Cannot Be Properly Combined 

Applicants reiterate and incorporate herein by reference the remarks concerning this 
same rejection that were provided in Applicants 1 reply filed on August 7, 2003. Specifically, 
Birkett does not disclose the use of core particles in which the cysteine residues at positions 
48 and 107 of SEQ ID NO: 134 (or at positions 48 and 1 10 of SEQ ID NO: 158) are either 
deleted or substituted with another amino acid, and does not disclose, suggest, or otherwise 
contemplate the use of a virus-like particle that is a dimer or a multimer of a polypeptide 
having the amino acid sequence characteristics recited in present claim 86. These 
deficiencies in Birkett are not cured by the disclosures of Mark or Zhou, alone or in 
combination, neither of which provides any suggestion or disclosure of the use of core 
particles having the amino acid sequence characteristics recited in present claim 86. Hence, 



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one of ordinary skill would have found no suggestion or motivation within the references 
themselves to have combined the disclosures of these references in order to attempt to make 
and use the presently claimed invention. Absent such suggestion and motivation, the 
references cannot be properly combined, and a prima facie case of obviousness cannot be 
established. See In re Fine, 5 USPQ2d 1596,1598 (Fed. Cir. 1988). Thus, the Examiner has 
not met the burden required to sustain a prima facie case of obviousness. 

Contrary to the Examinees contentions in the Office Action, Applicants are not 
arguing "against the references individually' 1 (Office Action at page 4). As the Examiner has 
stated, the present rejection is "based on [a] combination^ of references." Id. Applicants 
respectfully remind the Examiner, however, that the requisite motivation for combining 
references in attempting to establish a prima facie case of obviousness must be found either 
in the references themselves or in the knowledge generally available to one of ordinary skill 
in the art. See In re Kotzhab, 217 F.3d 1365, 55 USPQ2d 1313 (Fed. Cir. 2000). In the 
present case, for reasons discussed below, the disclosure of Mark provides no proper 
motivation to modify cysteine residues in HBV particles; hence, one of ordinary skill reading 
Birkett in view of Mark would have had no reason to have combined their disclosures to 
attempt to make and use the presently claimed invention. 

It therefore appears that the Examiner is attempting to find the required motivation to 
combine the cited references in Applicants' own specification rather than in the cited art. As 
the Federal Circuit has held numerous times, however, such a hindsight analysis is 
impermissible — instead, the Examiner must show suggestions, explicit or otherwise, that 
would compel one of ordinary skill to combine the cited references in order to make and use 
the claimed invention. See, e.g., Interconnect Planning Corp. v. Feil, 774 F.2d 1 132, 1 143 



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(Fed. Cir. 1985) ("When prior art references require selective combination by the [fact- 
finder] to render obvious a subsequent invention, there must be some reason for the 
combination other than the hindsight gleaned from the invention itself. 1 '); Fine, 5 USPQ2d 
at 1600 ("One cannot use hindsight reconstruction to pick and choose among isolated 
disclosures in the prior art to deprecate the claimed invention."); In re Pleuddemann, 
910 F.2d 823, 828 (Fed. Cir. 1990) (noting that use of an applicant's specification as though 
it were prior art to support an obviousness determination is legal error); In re Vaeck, 
947 F.2d 488, 493 (Fed. Cir. 1991) (holding that both the suggestion to combine references, 
and a reasonable expectation of success in making the claimed invention, "must be founded 
in the prior art, not in the applicant's disclosure."). The Board has also provided the same 
mandate on this issue: 

it is impermissible to use the claimed invention as an instruction 
manual or "template" to piece together isolated disclosures and 
teachings of the prior art so that the claimed invention may be 
rendered obvious .... a rejection based on § 103 must rest on a 
factual basis, with the facts being interpreted without hindsight 
reconstruction of the invention from the prior art. In making this 
evaluation, the examiner has the initial duty of supplying the factual 
basis for the rejection he advances. He may not, because he doubts 
that the invention is patentable, resort to speculation, unfounded 
assumptions or hindsight reconstruction to supply deficiencies in the 
factual basis. 

Ex parte Haymond, 41 USPQ2d 1217, 1220 (Bd. Pat. App. Int. 1996). Thus, the use of 
hindsight analysis in the present case is impermissible and cannot be used to attempt to 
establish a prima facie case of obviousness. 

B. The Reliance Upon Mark is Improper 

Applicants also respectfully assert that the present rejection improperly relies upon 



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the disclosure of Mark, because Mark is non- analogous art. Specifically, the disclosure of 
Mark relates to problems that are totally unrelated to the problems solved by the presently 
claimed invention. As one of ordinary skill would readily understand, and as the Examiner 
has stated (see Office Action at page 2, third paragraph, lines 6-8), the disclosure of Mark 
relates to methods for reducing or eliminating undesirable intermolecular crosslinking and 
intramolecular disulfide bridges that can be formed in recombinant proteins, by replacing or 
deleting cysteine residues that are non-essential for biological activity of the proteins. These 
problems are wholly unrelated to those solved by Applicants in making the presently 
claimed invention. 

As the disclosure of Mark clearly demonstrates (see Mark at col. 1, lines 30-44 and 
53-60), the problems to be solved in that reference can be summarized as follows: when a 
protein is microbially produced, its free cysteines are usually involved in the formation of 
intermolecular crosslinks and intramolecular disulfide bridges which lead to the formation of 
dimers and oligomers in the microbial extracts, which in turn renders purification and 
separation of the protein very laborious and time-consuming and necessitates several 
additional steps in purification, such as reducing and reoxidizing the protein. In addition, 
formation of multimers and random intramolecular disulfide bridges may lead to low 
specific biological activity. Hence, the problem to be solved in Mark is the propensity of 
recombinant proteins (particularly interferon-beta ("EFN-P")) to undergo random 
intermolecular crosslinking or intramolecular disulfide bridge formation, between cysteines 
on the protein molecules, to overcome the difficulties in purification and the reduction in 
biological activity that often accompany the formation of such cysteine-cysteine interactions. 

Unlike those of IFN-P described in Mark, however, the free cysteines of HBcAg are 



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not reported to undergo undesirable intermolecular crosslinking or intramolecular 
interactions via formation of disulfide bridges. Instead, the problem addressed by removal 
of the cysteine residues from HBcAg according to the presently claimed invention is quite 
different. Specifically, by the present invention Applicants have discovered that if free 
cyteines are present and accessible on a virus-like particle, these cysteines may provide 
binding sites for toxic products. See Specification as filed at pages 36-37, paragraphs 0143- 
0146. As described in the present specification, and as one of ordinary skill would readily 
understand, the administration to an individual of a HBcAg conjugate containing toxic 
components could lead to a potentially serious adverse reaction (see Specification as filed at 
page 36, paragraph 0144, final sentence). 

Additionally, as noted above, the disclosure of Mark relates to disulfide bonds 
formed between two cysteines, either within a single protein molecule (intramolecular 
disulfide bridging) or between two different protein molecules (intermolecular crosslinking 
via disulfide bridging). This situation is quite different from that in the presently claimed 
invention, where intermolecular crosslinks are formed via the interactions between cysteine 
residues and lysine residues when hetero-bifunctional cross-linkers are used. Specifically, in 
one embodiment of the presently claimed invention, a hetero-bifunctional cross-linker was 
employed which is reactive both with amino groups (e.g. , those on lysine residues) and with 
sulfhydryl groups (e.g., those on cysteine residues). In this scenario, the sulfhydryl groups of 
free cysteines on the core particle may react through cross-linkers linked to the amino groups 
of lysine residues in the vicinity, thereby resulting in a plurality of undefined cross-linked 
species of HBcAg monomers (i.e., a diverse mixture of cross-linked monomeric HBcAgs) 
(see Specification at page 37, paragraph 146). The presence of such a mixture of undefined 



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molecules creates great difficulty in assessing the coupling efficiency, and renders uncertain 
the exact composition of the vaccine. As noted above, however, the reaction leading to such 
crosslinked mixtures is different from that disclosed in Mark with respect to intermolecular 
crosslinking which is the result of the formation of disulfide bonds between two sulfhydryl 
groups on free cysteines (rather than between a sulfhydryl group and an amino group). 

There is a fundamental difference between a disulfide bridge such as that addressed 
in Mark, and a covalent link made using a hetero bifunctional agent such as that addressed 
by the presently claimed invention. As one of ordinary skill is aware, disulfide bridge 
crosslinks can be broken or rearranged by the use of thiol agents or reducing agents such as 
dithiothreitol (DTT) or p-mercaptoethanol. That is not the case for crosslinks between 
protein molecules or subunits that are formed via reaction between lysine and cysteine 
residues on the protein through use of a heterobifunctional agent such as MBS. In this case, 
if free cysteines from one subunit react with a lysine of another subunit within the same 
particle, dimers are produced. Those dimers may react further with one or more additional 
molecules or subunits, leading to the formation of increasingly large multimers within the 
same particle. As described in the present application (and as referenced above), these 
multimers lead to problems while analyzing the vaccine, e.g. , by SDS-P AGE, and cannot be 
broken or rearranged using thiol agents or reducing agents. Hence, the crosslinking problem 
addressed in Mark is significantly different (and indeed, significantly more easily solved) 
than the crosslinking problem addressed by the presently claimed invention. 

Since Applicants teach the use the compositions of the presently claimed invention 
as vaccines, the purity as well as the toxicity of the vaccines are of great concern in the 
present invention. In contrast, the disclosure of Mark does not address the toxicity of the 



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proteins produced therein, and only addresses purity from the standpoint of minimization of 
disulfide bridges rather than crosslinking between cysteine and lysine residues. Accordingly, 
one of ordinary skill would have found no guidance in Mark as to how to address the 
problem of the linkage of toxic compounds to proteins via free cysteine residues, nor the 
problem of minimizing the formation of cysteine-lysine crosslinks, since Mark was not 
directly concerned with those problems. 

Lastly, the proteins disclosed in Mark are of a very limited class. Specifically, a 
number of cytokines are disclosed in Mark as examples {see Mark at col. 3, line 65, to col. 4, 
line 1), and the bulk of the disclosure of that reference relates to IFN-P, TNF-a and IL-2. 
Mark does not even mention viral particles or components thereof, particularly HBcAg, let 
alone the cysteine properties of HBcAg. Indeed, Mark fails to recognize the specifics of 
particles formed from the assembly of multiple copies of the same or of a small number of 
different subunits. The proteins described in Mark, such as TNF-a, IFN-P or IL-2, may form 
dimers or trimers, but these complexes are far from being macromolecular assemblies of the 
type formed by HBcAg. 

For at least the foregoing reasons, Applicants respectfully assert that the disclosure of 
Mark is not analogous art with respect to the presently claimed invention — it is neither in 
the same field of endeavor (since it does not address the issues germane to cysteine-lysine 
crosslinking in viral particles, particularly HBcAg), nor is it reasonably pertinent to the 
particularly problem with which the present invention is concerned (since it does not address 
issues germane to linkage of toxic compounds to viral particles, particularly HBcAg, via free 
cysteines). Without being in the same field of endeavor and without being directed to the 
same problem as the presently claimed invention, Mark cannot be used to support an 



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obviousness rejection. See In re Clay, 966 F.2d 656, 658-9 (Fed. Cir. 1992); see also 
Ex parte Campbell, 21 1 USPQ575, 576 (USPTO BPAI 1980) ( M [a]lthough the solution to 
the problem would have been obvious once recognized, none of the prior art before us 
indicates any recognition of the existence of the problem."). Accordingly, Applicants 
respectfully assert that Mark would not be regarded as analogous art by one of ordinary skill 
in the fields to which the present invention pertains. For at least these reasons, the reliance 
upon Mark in making the present rejection is improper. 

C. The Disclosure of Zhou Does Not Cure the Deficiencies in Birkett 
Since Mark is not available as prior art, the present rejection can only be based on 
Birkett in view of Zhou. Applicants respectfully assert that this combination of references 
also does not render obvious the presently claimed invention, since Zhou does not cure the 
above-noted deficiencies in Birkett. Zhou discloses that all of the HBV core cysteines are 
non-essential for assembly of core particles. Zhou's focus is also on intermolecular disulfide 
bridges as in Mark, and their role in capsid assembly. Zhou does not disclose the specific 
deletion or substitution of CYS residues 48 and 1 10 of SEQ ID NO: 158 as required in the 
presently claimed invention. Therefore, one of ordinary skill in the art would not have taken 
Zhou into account for solving the problems solved by the present invention (as discussed 
above for Mark). Moreover, Zhou does not suggest or otherwise contemplate the deletion 
only of Cys48 and Cys 110 SEQ ID NO : 158, while retaining the other cysteine residues, e.g. , 
Cys61 . Hence, Applicants respectfully assert that Zhou cannot be properly combined with 
Birkett to render the claimed invention obvious. 



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D. The Cited Art Does Not Suggest Making the Necessary Molecular 
Modifications 

The Examiner is also reminded that it is axiomatic that, in order to support a prima 
facie case of obviousness, the prior art must suggest making the specific molecular 
modifications necessary to achieve the claimed invention. See In re Deuel, 51 F.3d 1552, 
1558 (Fed.Cir. 1995); In reLalu, 747 F.2d 703, 705 (Fed. Cir. 1984) ("[t]he prior art must 
provide one of ordinary skill in the art the motivation to make the proposed molecular 
modifications needed to arrive at the claimed compound."). That is, simply because "one 
can conceive a general process in advance for preparing an undefined compound [e.g., a core 
particle comprising a 'Hepatitis B amino acid sequence'] does not mean that a claimed 
specific compound [e.g. , a core particle comprising SEQ ID NO: 1 34 or SEQ ED NO : 1 5 8 (or 
portions thereof) which is modified so that the cysteine residues at positions 48 and 107 of 
SEQ ID NO: 134 (or 48 and 1 10 of SEQ ID NO: 158) are either deleted or substituted with 
another amino acid'] was precisely envisioned and therefore obvious." Deuel at 1559. 
Thus, in order for Birkett, Mark and Zhou to be suitable as references upon which to base a 
prima facie case of obviousness, there must be, at a minimum, a teaching or suggestion in 
these references that would have compelled one of ordinary skill in the art to include in their 
core particles a polypeptide having the amino acid characteristics recited in claim 86, which 
are substantially different from those of the HBV sequences disclosed in these references. 
As noted above, such a teaching or suggestion is wholly lacking in the cited references, 
alone or in combination — that is, the specific sequences recited in claim 86 (and the 
remaining claims depending therefrom that are the subject of the present rejection) are not 
disclosed, suggested or otherwise contemplated in the cited references, alone or in 



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combination. Therefore, in view of the holdings in Deuel and Lalu, the cited references 
cannot support a prima facie case of obviousness of the presently claimed invention. 

E. Summary 

In view of the foregoing remarks, Applicants respectfully assert that a prima facie 
case of obviousness has not been, and indeed cannot be, established on the basis of the 
disclosures of Birkett in view of Mark and Zhou. Reconsideration and withdrawal of the 
rejection of claims 86, 90-94 and 96-107 over these references therefore are 
respectfully requested. 

V. The Second Rejection Under 35 U.S. C. § 103(a) 

In the Office Action at page 3, the Examiner has rejected claim 95 under 35 U.S.C. 
§ 1 03(a) as being unpatentable over Birkett in view of Mark and Zhou and further in view of 
Neurath et al (U.S. Patent No. 5,565,548; document "B" cited on the Form PTO-892 
attached to Paper No. 11; hereinafter "Neurath"). Applicants respectfully traverse 
this rejection. 

Applicants reiterate and incorporate herein the remarks made above concerning the 
combination of the disclosures of Birkett, Mark and Zhou. Specifically, Birkett is deficient 
as a primary reference, Mark is nonanalogous art and therefore cannot be used in an 
obviousness rejection of the presently claimed invention, and Zhou does not cure the 
deficiencies of Birkett. Neurath only addresses immunogenic complexes containing certain 
HBV peptides and other immunogens, but does not indicate that such complexes present the 
immunogens in an ordered and repetitive array as required by the presently claimed 



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invention. Thus, one of ordinary skill would have found no motivation to combine the 
disclosure of Neurath with those of Birkett and Zhou (and Mark, which in any event is not 
available as a reference against the presently claimed invention). Hence, the disclosures of 
Birkett, Mark, Zhou and Neurath cannot be properly combined, and in any event would not 
have rendered the presently claimed invention obvious. 

In view of the foregoing remarks, Applicants respectfully assert that a prima facie 
case of obviousness has not been, and indeed cannot be, established on the basis of the 
disclosures of Birkett in view of Mark and Zhou and further in view of Neurath. 
Reconsideration and withdrawal of the rejection of claim 95 over these references therefore 
are respectfully requested. 

VI. The Third Rejection Under 35 U.S. C. § 103(a) 

In the Office Action at page 3, the Examiner has rejected claims 108-110 under 
35 U.S. C. § 1 03(a) as being unpatentable over Birkett in view of Mark and Zhou and further 
in view of Davis et aL (WO 98/40100; document "N" cited on the Form PTO-892 attached 
to Paper No. 11; hereinafter "Davis"). Applicants respectfully traverse this rejection. 

Applicants reiterate and incorporate herein the remarks made above concerning the 
combination of the disclosures of Birkett, Mark and Zhou. Specifically, Birkett is deficient 
as a primary reference, Mark is nonanalogous art and therefore cannot be used in an 
obviousness rejection of the presently claimed invention, and Zhou does not cure the 
deficiencies of Birkett. Davis only addresses immunogenic complexes containing certain 
HBV peptides and alum as an adjuvant, but does not indicate that such complexes present 
the immunogens in an ordered and repetitive array as required by the presently claimed 



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invention. Thus, one of ordinary skill would have found no motivation to combine the 
disclosure of Davis with those of Birkett and Zhou (and Mark, which in any event is not 
available as a reference against the presently claimed invention). Hence, the disclosures of 
Birkett, Mark, Zhou and Davis cannot be properly combined, and in any event would not 
have rendered the presently claimed invention obvious. 

In view of the foregoing remarks, Applicants respectfully assert that a prima facie 
case of obviousness has not been, and indeed cannot be, established on the basis of the 
disclosures of Birkett in view of Mark and Zhou and further in view of Davis. 
Reconsideration and withdrawal of the rejection of claims 108-110 over these references 
therefore are respectfully requested. 

VIL The First Obviousness-Type Double Patenting Rejection 

In the Office Action at page 4, the Examiner has provisionally rejected claims 86 
and 90-1 10 under the judicially created doctrine of obviousness-type double patenting as 
being unpatentable over claims 100-1 14 of commonly owned, co-pending U.S. Appl. No. 
10/050,902 ("the f 902 application"). Applicants respectfully traverse this rejection. 
However, to expedite prosecution, Applicants respectfully request that this rejection be held 
in abeyance until the identification of otherwise allowable subject matter in the present 
application, at which time Applicants will consider filing a properly executed Terminal 
Disclaimer Under 37 C.F.R. § 1.321(c). 



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VIIL The Second Obviousness-Type Double Patenting Rejection 

In the Office Action at page 4, the Examiner has provisionally rejected claims 86 and 
90-1 10 under the judicially created doctrine of obviousness-type double patenting as being 
unpatentable over claims 14-1 6 of the '902 application. Applicants respectfully traverse this 
rejection. However, to expedite prosecution, Applicants respectfully request that this 
rejection be held in abeyance until the identification of otherwise allowable subject matter in 
the present application, at which time Applicants will consider filing a properly executed 
Terminal Disclaimer Under 37 C.F.R. § 1.321(c). 

IX. Conclusion 

All of the stated grounds of rejection have been properly traversed. Applicants 
therefore respectfully request that the Examiner reconsider all presently outstanding 
objections and rejections and that they be withdrawn. 

Applicants believe that a full and complete reply has been made to the outstanding 
Office Action and, as such, the present application is in condition for allowance. If the 
Examiner believes, for any reason, that personal communication will expedite prosecution of 
this application, the Examiner is invited to telephone the undersigned at the number 
provided. 



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Prompt entry and consideration of the present Amendment and Reply, and allowance 
of all pending claims, are earnestly solicited. 



Respectfully submitted, 

Sterne, Kessler, Goldstein & Fox p.l.l.c. 

Brian J. Del Buono 
Attorney for Applicants 
Registration No. 42,473 

Date: 

1 100 New York Avenue, N.W. 
Washington, D.C. 20005-3934 
(202) 371-2600 

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